
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)13564-5
10.1016/j.heliyon.2024.e37533
e37533
Review Article
A comprehensive review of advanced focused ultrasound (FUS) microbubbles-mediated treatment of Alzheimer's disease
Rouhi Nadiyeh nrouhi@umc.edu
a
Chakeri Zahra b
Ghorbani Nejad Behnam c
Rahimzadegan Milad d
Rafi Khezri Mohammad e
Kamali Hossein kamalih@mums.ac.ir
fg⁎
Nosrati Rahim nosratirahim@gmail.com
rahim_nosrati@gums.ac.ir
h⁎⁎
a Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, 39216, USA
b Cardiothoracic Imaging Section, Department of Radiology, University of Washington, Seattle, WA, USA
c Department of Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
d Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
e Urmia University of Medical Sciences, Urmia, Iran
f Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
g Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
h Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
⁎ Corresponding author. Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. kamalih@mums.ac.ir
⁎⁎ Corresponding author. nosratirahim@gmail.comrahim_nosrati@gums.ac.ir
06 9 2024
30 9 2024
06 9 2024
10 18 e3753318 11 2023
27 8 2024
4 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, memory loss, and cognitive impairment leading to dementia and death. The blood-brain barrier (BBB) prevents the delivery of drugs into the brain, which can limit their therapeutic potential in the treatment of AD. Therefore, there is a need to develop new approaches to bypass the BBB for appropriate treatment of AD. Recently, focused ultrasound (FUS) has been shown to disrupt the BBB, allowing therapeutic agents to penetrate the brain. In addition, microbubbles (MBs) as lipophilic carriers can penetrate across the BBB and deliver the active drug into the brain tissue. Therefore, combined with FUS, the drug-encapsulated MBs can pass through the ultrasound-disrupted zone of the BBB and diffuse into the brain tissue. This review provides clear and concise statements on the recent advances of the various FUS-mediated MBs-based carriers developed for delivering AD-related drugs. In addition, the sonogenetics-based FUS/MBs approaches for the treatment of AD are highlighted. The future perspectives and challenges of ultrasound-based MBs drug delivery in AD are then discussed.

Highlights

• Alzheimer's disease (AD) is the most prevalent neurodegenerative disorders in people over the age of 65.

• The selective permeability of BBB restricts the therapeutic potential of drugs in the AD therapy.

• Focused ultrasound (FUS)-induced microbubbles (MBs)-based drug delivery has attracted a lot of interest for AD treatment.

• This review mainly focuses on recent developed FUS-induced MBs-based approaches for AD treatment.

• Future perspectives and challenges of FUS-induced MBs-based drug delivery are also discussed.

Keywords

Neurodegenerative diseases
Alzheimer
Focused ultrasound (FUS)
Microbubbles
Drug delivery
Sonogenetics
==== Body
pmc1 Introduction

Recently, neurodegenerative diseases have become a major concern, especially because of serious damage to the central nervous system (CNS) that is often difficult to treat [[1], [2], [3]]. These disorders encompass a broad spectrum of diseases with deep-seated and severe symptoms, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other brain disorders [1,[4], [5], [6]]. Alzheimer's disease is the most common cause of dementia which affects a person's ability to function via a gradual decline in memory, thinking, behavior, and social skills [[7], [8], [9], [10]].

Despite the huge burden and the impact on the patients, there is no definitive cure for AD and thus, developed treatment methods are needed. Significant progress in biotechnology and nanotechnology over the past two decades has yielded some important insights about the basic biology and clinical pathophysiology of AD, leading to more effective therapeutic approaches [[11], [12], [13]]. The novel strategies to be able to improve the permeability of the blood-brain barrier (BBB) have attracted a lot of interest for AD related drug delivery [14,15]. Recently, focused ultrasound (FUS)-induced drug delivery has opened new prospects because it directly delivers the drugs of AD into the brain via the penetration of the BBB [16,17]. FUS in combination with the cavity behavior of microbubbles (MBs) can deliver the drug-loaded MBs to the target site in the deep regions of the brain [[18], [19], [20]].

In the present review, a comprehensive approach to understanding the FUS-induced MBs-mediated drug delivery for the treatment of AD and the challenges to be considered in the development of these strategies are discussed.

1.1 Alzheimer's disease and therapeutic approaches

AD refers to one of the major causes of senile dementia with properties including progressive neurodegeneration, cognition impairment, neuronal and axonal loss followed by memory loss [8,21,22]. Progressive cognitive and memory impairment with personality changes in severe AD can lead to dementia and even death [8,23,24]. Memory and cognitive impairment are the main symptoms related to dementia, and it is commonly due to the decrease in acetylcholine (ACh) function in the neurons of the CNS [25]. Aging is among the most important known risk factors for most chronic illnesses, including AD [26]. The increasing population of the elderly in the world is associated with the prevalence of AD [[27], [28], [29]]. The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of phosphorylated tau protein in the brain (hippocampus) cells are considered the hallmark lesions of AD [8,27,30,31]. In addition, mitochondrial dysfunction and neuroinflammation (which ultimately leads to neuronal loss) can play a vital role in AD [32,33]. Some drugs (Not approved) have been introduced for AD, but these drugs are often not effective in completely treating the symptoms and their effectiveness decreases over time [[34], [35], [36]]. Therefore, the novel therapy approaches that can provide effective treatment and remarkable advantages for patients who suffer from these devastating disorders are of utmost importance [26,34].

Challenges in treating AD have partially arisen from difficulties in penetrating the BBB [37,38]. The BBB has a selective permeability and preventing function that tightly controls the entry and exit of exogenous substances especially harmful molecules, which is vital in healthy people [14,37]. This barrier does not allow the required amount of the drug to be delivered into the brain, restricting their potential therapeutics in neurodegenerative diseases [14,38,39]. Recently, micro- and nano-sized carriers have shown great potential as precision medicines that can efficiently penetrate into the brain by crossing, avoiding, or disrupting the BBB and increasing the targeting ability of drugs [14,15]. Regarding, MBs combined with FUS gained special advances as a potential permeable option across BBB [18,40].

1.2 Blood-brain barrier (BBB)

The BBB is a selective semi-permeable membrane between the blood and the interstitium of the brain. BBB regulates the entering of chemicals and drugs into the brain. Physiologically, the BBB is formed by brain microvascular endothelial cells (BMEC), pericytes, and astrocytes (Fig. 1). This structure restricts the permeability of delivered drugs from the blood into the brain and makes it difficult to treat many brain disorders effectively. The presence of occludin- and claudin-based tight and adherens junctions, vascular endothelial (VE)-cadherin, and zonula occludens-1 (ZO-1) accessory protein play a role in the transcytosis of molecules through the BBB [41,42].Fig. 1 The structure of Blood-brain barrier (BBB).

Fig. 1

The pathophysiology of AD is closely related to BBB dysfunction. Changes and dysfunction in the BBB structural components (astrocytes, pericytes) and tight junctions between endothelial cells can cause Aβ accumulation in the brain and increase oxidative stress and beta- and gamma-secretase activity, resulting in Aβ pathology. This condition continues to destroy neurons and glial cells as well as damage the neural network that leads to cognitive decline and the onset of dementia [[43], [44], [45]].

Several approaches have been developed for getting around the BBB, such as intracerebral/intraventricular injections, intranasal delivery, and chemical mediation. However, some drawbacks, such as low delivery, side effects on healthy tissue, and systemic cytotoxicity have been observed [41,45]. Non-invasive methods such as MBs-induced FUS can be alternative options for controlled, reversible, and safe permeability of BBB.

1.3 Microbubbles (MBs)

MBs are a type of microspheres that are structurally contained a nano-sized shell with different compounds and a gas-filled core [46,47]. The shell may be composed of different compounds such as surfactants, proteins, lipids, polymers, which is separated the encapsulated gas from the surrounding aqueous medium (Fig. 2a and b) [20,48,49]. MBs are typically between 0.5 and 10 μm in diameter which allows to circulate in the micro-vessels and capillaries all over the body [46,48]. Changes in core and shell properties determine the strength, acoustic properties, thermal conductivity, and buoyancy of MBs [50].Fig. 2 a) The structure of typical MBs with different shell compositions, b) Drug attachment strategies in MBs mediated drug delivery. Reprinted with permission from Refs. [49,51].

Fig. 2

MBs have widespread application in life science, industry, and medicine especially MBs have been used in drug delivery [52]. MBs can avoid the drugs degradation in the blood circulation and avoid uptake by nonspecific cells or tissues. At the target site, the released drug from MBs can penetrate into cell under ultrasound [53]. The lipophilicity of MBs can facilitate drug penetration into the BBB, but the large size of MBs can be limited the easily cross the barrier [54]. Concomitant use of FUS with MBs can eliminate this problem, which facilitates the penetration of MBs [47]. It has also been proven that this change in BBB permeability is reversible and without serious side effects [18,55].

1.4 Focused ultrasound (FUS)

Current strategies to deliver molecules into the brain can be categorized as invasive and non-invasive [38,56]. The invasive manner directly administrated the therapeutic agents into the brain through intracerebral or catheter-guided injection, and opening the tight junctions of endothelial cells that are exposed to a hypertonic solution [38,57]. The invasive methods increase the risk of infection, possible injury of brain tissues, and uncontrolled release of drugs [58]. Therefore, the non-invasive approaches that can deliver the therapeutics to the brain via intravenous injection or intranasal administration are commonly preferred. The non-invasive neuromodulation technologies are one of the most promising parts in the development of therapies for neurological diseases [59,60]. However, problems such as limited penetration depth and spatial targeting are seen in common non-invasive approaches, containing transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) [59,61].

FUS is a non-invasive strategy for drug/gene delivery to the brain by using ultrasonic energy, which can open the BBB transiently, manipulate the function of cells and proteins, and facilitate the drug's delivery to the target cells with high accuracy [16,17,62]. Studies have shown that FUS can overcome the low penetration of traditional non-invasive methods due to the penetration of sound waves into soft tissue and bone and its high ability to modulate nerve activity in deep areas of the brain with millimeter spatial accuracy. The ultrasound waves used in FUS have a frequency of about 2–18 MHz, which is 100 times more than the human hearing range [63]. The higher frequency (shorter wavelength/higher energy) of the ultrasound waves can penetrate the tissue. A new technology called sonogenetics, allows ultrasound to be directly related to cellular activity [64,65]. The speed and penetration rates of FUS are related to the compressibility of the tissue and its density, which is called different sound impedance [65]. FUS in connection with the cavity behavior of MBs can transport the biomolecules and drugs through various cellular and tissue barriers [66]. In this line, recent reports suggest that the FUS-induced MBs-related technology could be used to treat neurodegenerative diseases [17,67].

2 FUS-induced MBs-based drug delivery mechanism

Cavitation, the mechanical effects of FUS, is the main cause of the disruption of the BBB [68]. The cavitation effects from the circulating MBs during irradiation with FUS sonication are the basis of FUS-induced BBB permeability [47,67]. This phenomenon causes the increase of endocytosis/transcytosis, and paracellular passing via reformed tight junctions or through the endothelium cell membrane channels [17,18]. Stable or inertial cavitation are two forms of acoustic cavitation. In stable cavitation, the acoustic microstreaming and pushing/pulling of MBs on the membranes of adjacent cells lead to pores creation and desired BBB permeability [65,69]. Inertial cavitation can potentially disrupt the membrane by the implosion of the MBs and the formation of jets [65].

Selective and regional permeability is a unique advantage of FUS/MBs disruption of the BBB, which allows for improved local delivery of drugs to the brain [70]. In the FUS/MBs technique, low-frequency ultrasound waves are administrated transcranially, ultimately leading to oscillation and concentration of MBs on the capillary walls, which in turn the expansion and contraction of MBs, leading to loosening of the tight junctions between endothelial cells [16].

The intravenous direct administration of the drug or release of the drug locally using drug-loaded MBs provides a high concentration of the drug at the site of BBB disruption, which is needed for the FUS-assisted drug delivery via BBB [17,71]. FUS in combination with intravascular MBs can open tight junctions, create endothelial cell openings, and improve endocytosis and transcytosis [72]. The exact mechanisms have still not been fully clarified, but in the presence of FUS, MBs oscillate and apply biomechanical forces on the blood vessel wall, which assist drug delivery through the capillary wall by transcellular or paracellular routes [73]. Based on preclinical observations, three routes were proposed for FUS/MBs-assisted drug delivery at the BBB including paracellular transportation of drug by mechanical forces of MBs, increasing in the number of intracellular vesicles and upregulation of endo- and transcytosis, and limitation of drug efflux at the BBB by decreasing of expression of P-gp at brain microvascular endothelial cells (BMEC) (Fig. 3a and b) [74].Fig. 3 a) role of BBB barrier in the penetration of drugs into brain, b) FUS-induced MBs-based drug delivery to the brain mechanism. Reprinted with permission from Ref. [75].

Fig. 3

Cavitation of bubbles during irradiation with an ultrasound field can enhance the vascular permeability, facilitating intracellular delivery of small molecules from the blood vessels, a process named as sonoporation. Although the detailed mechanisms of sonoporation are not completely understood, sonoporation, like electroporation, can generate transient pores in cell membranes allowing drug uptake by the cell [76,77]. Sonoporation can also improve the delivery of genes and drugs to the target cells, even in deep tissues [65,76].

Evaluation of the concentration and amount of therapeutic agents that can be delivered to different brain regions is an important aspect of assessing the efficacy of FUS/MBs-released anti-AD drug delivery [78]. Both qualitative and quantitative approaches can be used to analyze the concentration of drugs delivered to the brain. The efficiency of drug delivery and targeting in the brain is usually presented in indirect form. Radioactivity, fluorescence, and UV absorption are used to quantify the drug concentration in the brain. It is difficult to quantitatively estimate the absolute amounts of drug that have reached the brain. The uptake of the drug in the brain is presented as a relative value [79,80]. Basic histologic stains, such as H&E and Nissl, have been used to assess the effects of FUS/MB on tissue health [81]. A quantitative pharmacodynamic analysis can be provided based on the changes in the T1 relaxation after gadolinium injection and quantitative drug concentration maps [78].

3 Role of the MBs properties in the FUS-induced BBB opening

The performance of MBs-based drug delivery is affected by their physicochemical properties such as size, morphology, stability, surface modification, drug loading capacity, and drug release content. When performing the process, some parameters must be considered, such as controlling size, stability, and drug leakage from the MBs. The size of the MBs is usually about 0.5–10 μm, and their size makes them easier to swallow and facilitates the mechanism of drug delivery to the body. The size of the MBs in the range of micrometers may be limited to cross the endothelium, so, a smaller size particle would be preferable [82]. FUS-induced micro-to-nano conversion considerably overcomes the limitation of conventional MBs drug delivery methods [83].

To clarify the role of size of MBs in the FUS-dependent opening BBB, two sets of experiments were carried out on monkeys and mice. Before sonication of the right hippocampus with FUS, 67 mice intravenously received MBs either 1–2, 4–5, or 6–8 μm in diameter. The results showed that when the bubble diameter was similar to the capillary diameter, BBB opened with nonlinear bubble oscillation without inertial cavitation. In monkey model experiments, in all cases with 4–5 μm diameter bubbles, the BBB was opened. This study demonstrated the bubble volume across from BBB was dependent on both the bubble diameter and acoustic pressure [84].

However, the effects of encapsulated MBs on stability and drug delivery efficacy have not been identified, their gaseous core of MBs allows the loading of sufficient drugs and their surrounding shell protect drugs from fast release. Moreover, when drugs are dissolved within the lipid layer of the shell or directly merged into the shell, MBs can protects them from degradation and clearance [85]. To evaluate how loaded drugs alter the stability of MBs, FUS imaging ability, and efficacy of the drug deliver efficacy to the brain, MBs with the same lipid shells can be encapsulated with different FDA-approved gases such as sulfur hexafluoride (SF6), perfluoropropane (C3F8), and perfluorobutane (C4F10) [86]. The interactions between MBs and FUS in the biodistribution of drug within the brain depend on the frequency and power of FUS beams and the dose of MBs [85]. Low-intensity FUS opens the BBB transiently and reversibly, which is followed by the opening of tight junctions of brain endothelial cells and transcellular transportation. These phenomena facilitate the biodistribution of drug within the brain [87]. In a study, the detection of BBB opening following the FUS was assessed by intravenous injection of an NRI agent (gadolinium) as an opening-tracer, which normally does not cross the BBB. The results showed a high amount of the opening volume and gadolinium in the grey matter and an increased FUS-induced permeability and drug concentration with the acoustic pressure [78]. In rodents, physiological properties of the BBB, such as opening volume, permeability, therapeutic agents’ concentration, and reversibility timeline should be addressed. So, thoughtful MBs-related pharmacokinetics and physiological variation are vital for emerging safe and stable FUS/MBs treatment protocols [88].

The coating of MBs surface by various polymers, proteins, lipids, or surfactants possesses different properties to MBs consisting of charge, functionality, and hydrophobicity [89]. These are critical hallmarks for their performances and interaction with target markers. Although the limited surface area and shell thickness of MBs limit their loading capacity, the functionalization of MBs can overcome this shortcoming. Drugs can bind to the MBs shell through specific ligands. Thus, the functional groups are effective criteria for the encapsulation and loading of sufficient content of drugs on the MBs surface. In addition, the MBs that are surface-engineered with functional groups are capable of conjugation with preferred ligands or proteins for site‐specific delivery. Lipid MBs are often preferred to polymer MBs due to the permeability of lipid-based material across BBB and their interaction with ultrasound waves. Although the shell of polymeric and lipid-based MBs cracks at high ultrasound pressure, through which the loaded drug can leak the lipid-based MBs become somewhat more resistant to low ultrasound [20].

In addition to the size and type of MBS, the consistent BBB opening is highly related to the dose, and delivery route of MBs [50,54]. In the main protocols of FUS, MBs are intravenously injected with a dynamic dose, permanently rising and falling [90]. Furthermore, the clearance of MBs limits the penetrated drug from opened BBB. Variability in bubble concentrations can pose a potent challenge for MBs-mediated drug delivery [50,91]. MBs at an acceptable serum concentration address these restrictions in the treatment time.

4 MBs as contrast agents in FUS-based imaging of AD

Recently, the serve of MBs as ultrasound contrast enhancement agents has extensively developed in AD imaging. In a study, the left hippocampus of the AD APP/PSI mice was sonicated and the MBs were injected intravenously into the animals. Brain images were obtained before and after injection of Gadolinium (Gd) using MRI. MRI images showed that the BBB was opened on the first day and closed on the second day, although the duration and extent of the opening were different in different regions. The results of this study displayed that FUS can induce the BBB opening and internalization of Gd-loaded MBs in brain cells [92]. MRI technique has been used to characterize AD by diagnosis and checking of amyloid plaques, but invasive interventions are needed to penetrate the contrast agents into the BBB. In a work, unfocused ultrasound in combination with clinically approved MBs was employed for transiently opening the BBB, to determine amyloid plaques in the brain of an APP/PS1 transgenic mouse model of amyloidosis after intravenous injection of a contrast agent. The fabricated method can detect amyloid plaques with a high in-plane resolution at 32 min imaging time. The results showed similar sensitivity to standard brain MRI whenever a contrast agent was injected via intra-cerebra-ventricular [93].

In most studies, the researchers have been provided a proper MBs-based theranostic agent for the treatment diagnosis of AD by the combination of MBs conjugate with chemotherapeutic agents. Magnetic resonance-guided focused ultrasound (MRgFUS) coupled with injected MBs is an emerging surgical technology for noninvasive brain treatments that transiently open the BBB with a high degree of spatial and temporal specificity [94]. It was found that the use of FUS in combination with MBs allowed a small fluorescent agent and anti-Aβ antibody as a large molecule to enter the brain in transgenic AD mice. The change in the permeability of the BBB by FUS provided a condition for the delivery of both molecular imaging and therapeutic agents to target the Aβ [95].

5 FUS-induced delivery of drug-loaded MBs for AD therapy

Biomarkers-based diagnosis and treatment of diseases are the most reliable ways to help physicians prevent or limit disease progression. AD-related biomarkers such as Aβ, Tau protein, and apolipoprotein E4 (ApoE 4) have been usually used for the determination of AD in blood and cerebrospinal fluid (CSF) [96,97]. In this line, these specific AD biomarkers are the basis of drug delivery to the brain by FUS/MBs for AD therapy (Table 1).Table 1 FUS-induced delivery of drug-loaded MBs for AD therapy.

Table 1Ultrasonic parameters	Microbubbles properties	Animal model	Therapeutic agents	Target	Ref.	
Acoustic pressure	Frequency (MHz)	Duration	Duty cycle (%)	PRF (kHz)	
0.4–0.6 MPa	1.14 MHz	2 min	0.5 %	–	1 μm	Mice model of AD	PEG coated, brain-penetrating nanoparticles	Amyloid-beta (Aβ) plaque	[98]	
–	–	600 s	–	–	poly-α-cyanoacrylate (pBCA)-based MBs	APP/PS1 Mice model of AD	Quercetin-modified sulfur nanoparticles	[19]	
0.6 MPa	1.0 MHz	1 min	10 %	10 Hz	300 nm
PLGA-lipid hybrid	APP/PS1 transgenic mice	Nanosized exosome	[99]	
0.41–0.5 MPa	400 kHz	60 s	–	1 Hz	SonoVue® SF6-filled MBs	APPswe/PSEN1-dE9 transgenic mice	GSK-3 inhibitor	[100]	
0.3 MPa	0.558 MHz	2 min	–	1 Hz	0.16 ml/kg	TgCRND8 mice model of AD	Anti‐Aβ antibody BAM10	Amyloid-beta (Aβ) plaque	[101]	
0.8 MPa	1 MHz	20 s	–	1 Hz	SonoVue 0.05 ml/kg	New Zealand rabbits	BC-10 anti-Aβ antibody	[102]	
	0.55 MHz	120 s		1 Hz	0.04 ml/kg	TgCRND8 mice model of AD	BAM-10 Aβ-antibody and scyllo-inositol	[103]	
Constant	1.68 MHz	2 min	–	1 Hz	–	TgCRND8 mouse model of amyloidosis	intravenous immunoglobulin (IVIg)	[104]	
0.7 MPa	1 MHz	3 min	10 %	10Hz	1.885 μm
Lipid shell	APP23 mouse model of AD	Aducanumab antibody	[105]	
–	–	–	–	–	–	APP/PS1dE9 mice	anti-pGlu3 Aβ mAb
antibody	[106]	
0.33 MPa	2 Hz	100 s	–	–	Optison™ MBs	APP/PS1dE9 mice	anti-pGlu3 Aβ
antibody	[107]	
0.45 MPa	1.5 MHz	1 min	–	10 Hz	1.4 μm	rTg4510 Mouse Model		Tau protein	[108]	
0.42 MPa	1 MHz	60 s	2 %	1 Hz	10 μm	tau transgenic mice		[109]	
0.64 MPa	1 MHz	2 min	10 %	1 Hz	4–8 μm lipid shell	Mice model of AD		[52]	
25 % of the value	1.68 MHz	120 s	–	1 Hz	0.02 ml/kg	TgCRND8 mice	TrKA agonist D3	TrKA receptor	[110]	

5.1 Amyloid β (Aβ)

Most studies of FUS/MBs-induced drug delivery to AD treatment have been focused on the permeability of the BBB and subsequently reducing the accumulation of amyloid plaques. Accumulation of Aβ isoforms including insoluble Aβ42 and soluble Aβ40 has a direct effect on the development and progression of AD [[97], [111], [112]]. Age-related changes interfere with lymphatic clearance, leading to Aβ accumulation and eventual AD. Based on this, the FUS/MBs combination improved brain-to-cerebrospinal fluid (CSF) Aβ drainage in a mouse model of dementia [113]. Regarding this, FUS/MBs may enhance Aβ entry into the circulation system resulting in increased Aβ clearance by the liver and kidneys. It can be said that MBs treatment may lead to enhanced non-amyloidogenic pathway and suppressed amyloidogenic pathway. It would be great to investigate the effect of MBs on different aspects of Aβ-related pathogenesis including Aβ production pathways and their clearance in future research.

5.1.1 Nanoparticles and therapeutic agent's delivery

Nance et al. investigated a non-invasive approach including MRgFUS, MBs, and polymeric nanoparticles (NPs) as a therapeutic agent with penetrating ability into the brain parenchyma. The coating of brain-penetrating NPs (BP-NPs) with low-molecular-weight poly(ethylene glycol) (PEG) provides long-circulating and stable BP-NPs. However, PEGylation covers NPs and increases their interactions with cells, but limits their cell uptake or passage across intact BBB. MRgFUS can improve the accumulation and spread of BP-NPs in specific areas of the brain. The results showed that the FUS/MBs coupling could deliver 60 nm PEGylated BP-NPs to the brain parenchyma with a 10-fold slower diffuse in normal rat brain tissue. This strategy suggests a potential to improve efficacy, reduce side effects, and provide sustainable drug delivery in the treatment of many CNS-related diseases, especially AD [98].

In a study, the therapeutic potentials of FUS-induced BBB opening were evaluated on the delivery of GSK-3 inhibitor (AR-A014418) and reduction of Aβ plaque synthesis for AD treatment in an AD mice model (Fig. 4a). FUS-mediated BBB opening on APPswe/PSEN1-dE9 transgenic mice was performed unilaterally, with the contralateral hemisphere serving as a control. The immunohistochemistry (IHC) results revealed the reduction of GSK-3 activity up to 61.3 % after FUS-mediated GSK-3 inhibitor delivery. A significant Aβ-plaque reduction up to 31.5 % was also confirmed by autoradiography [100]. Lipid nanoparticles (LNP)-based mRNA delivery has become a novel therapeutic approach. Recently, FUS/MBs-mediated BBB opening can enhance the delivery of mRNA-encapsulated LNP (mRNA-LNP) through BBB to the brain. In a study, it was demonstrated that by applying FUS/MBs, plasmid DNA delivery and exogenous protein (luciferase) expression by mRNA-LNP in the microglia and CD31-positive endothelial cells can be observed, confirming the NPs delivery by BBB opening (Fig. 4b) [114].Fig. 4 a) The reduction of Aβ plaque synthesis by FUS-induced BBB opening and the delivery of GSK-3 inhibitor (AR-A014418), b) FUS/MBs-mediated delivery of mRNA encapsulated-LNP (mRNA-LNP) through BBB in an AD model. Reprinted with permission from Refs. [100,114].

Fig. 4

A nano-system based on MBs in combination with FUS was constructed to promote the crossing of Quercetin-modified sulfur NPs across the BBB (Fig. 5a). After exposure to ultrasonic pulses, the system is immediately destroyed resulting in improved permeability of the blood vessels and brief opening of the BBB because of the "sonoporation" effect. In addition, after the destruction of the MBs, the nanodrugs embedded in them were released and accumulated in the parenchymal tissue of the brain. Because of instantaneous accumulation in the brain, nanodrug efficiently reduces inflammatory response, apoptosis, oxidative stress, and calcium homeostasis imbalance which is mediated by protecting neuron cells and endoplasmic reticulum stress, thus improving AD. Significant improvement in memory and learning ability was determined without obvious side effects [19]. Exosomes are nano-sized extracellular vesicles that are secreted by different cells of the central nervous system and can be involved in the removal of intracellular material. In AD, increases in Aβ levels can impair the exosome-mediated Aβ clearance pathway. Regarding the role of FUS in the degradation of Aβ, in a study, FUS/MBs were applied for targeted exosome delivery across BBB (Fig. 5b). After FUS, FUS-stimulated HA cells were collected to characterize exosomes. The oligomeric Aβ42 toxicated SH-SY5Y cells were employed for the investigation of the neuroprotective effect of FUS-stimulated HA cells. FUS demonstrated a 5-fold increase in the exosome release from human astrocytes. The decrease of Aβ plaque in APP/PS1 animals following treatment revealed the therapeutic potential of FUS-stimulated HA cells and demonstrated its neuroprotective potential in reversing oligomeric Aβ-induced cytotoxicity [99].Fig. 5 a) The BBB crossing of quercetin-modified sulfur NPs/MBs in combination with FUS, b) FUS/MBs-mediated exosome delivery across BBB for Aβ clearance. Reprinted with permission from Refs. [19,99].

Fig. 5

5.1.2 Anti-Aβ antibody delivery

Anti-amyloid mAbs are the first disease-modifying therapies for AD that are directed against the amyloid-β (Aβ) peptide resulting in the slowing of the progression of AD. Over the past years, several mAbs have been engineered to bind and clear Aβ such as bapineuzumab, solanezumab, gantenerumab, crenezumab, and aducanumab [115,116].

In a TgCRND8 mouse model of AD, MRgFUS in combination with MBs was used to deliver BAM-10, an anti-Aβ antibody. In this study, Gd was used as a contrast agent. The antibody was injected into the treated animals at the same time as the ultrasound was applied to a hemisphere of the brain. The results showed that only mice that were exposed to FUS had significant amounts of the antibody in their brains. It was also found that four days after treatment, the level of Aβ in the brains of animals significantly decreased [101]. Alecou et al. reported the treatment of AD in a New Zealand White rabbit model based on MRIgFUS-MB facilitated to entry of the BC-10 anti-Aβ antibody into the brain and its binding to Aβ plaques. Their results revealed a reduction in the number of plaques and elimination of Aβ plaques [102]. In a study, the effect of a combination treatment including initial MRIgFUS/MBs-mediated delivery of BAM-10 Aβ-antibody and scyllo-inositol was investigated on reducing Aβ load through microglial phagocytosis in a TgCRND8 mouse model of AD. After 30 days, a significant reduction of loaded-Aβ and astrocyte activation in the hippocampus and the cortex, and an increase in phagocytic activity of microglia, which relates to Aβ clearance [103].

Intravenous immunoglobulin (IVIg), a centrally and peripherally immunomodulatory, is a human blood product consisting of polyclonal antibodies that can reduce Aβ-related AD. In a study, the potential improvement in the delivery of IVIg to the hippocampus, promotion of neurogenesis, and reduction of amyloid plaque pathology following FUS were investigated. The result demonstrated the FUS can significantly increase the IVIg levels and hippocampal neurogenesis through increased BBB permeability along with a considerable reduction of in amyloid plaque the targeted hippocampus of TgCRN8 mice. The down-regulation of proinflammatory cytokines such as tumor necrosis factor α (TNFα) in the hippocampus confirmed the FUS/MBs-induced inflammation [104]. The results of clinical trials show that Aducanumab as an anti-Aβ can reduce the pathology of amyloid. It has also been shown that this antibody must reach a certain level of accumulation in the brain to improve cognition. In a study, Aducanumab analog efficacy was investigated by FUS merged with intravenously injected MBs in APP23 mice. The results showed that the treatments reduce plaques in the hippocampus, but no significant improvement was seen in combination therapy. However, in the cortex, only combination therapy caused a significant reduction in plaque. It was also found that cognitive improvement was seen only in the combination group and the amount of Aducanumab in this group was 5 times higher than the other groups [105].

A study has shown monoclonal antibody (mAb) reduces the plaques of Aβ and pGlu3 Aβ in APP/PS1dE9 mice by targeting the toxic species of Aβ. In this study, the effect of mAb 07/2a on Aβ clearance and cognition was evaluated through FUS/MBs-induced BBB opening. The result showed that FUS treatment increased mAb levels in the brain, reduced the accumulated hippocampal Aβ, and improved cognition [106]. In another study, the FUS/MBs procedure was employed in the AD model of amyloidogenesis to improve intravenous delivery of mAb 07/2a as an Fc-competent anti-pGlu3 Aβ through the BBB. Pyroglutamate-3 amyloid-β (pGlu3 Aβ) is a form of Aβ with pathogenic specification found in vascular deposits and cerebral amyloid plaques. The results of this study showed that the use of FUS increased the delivery of 07/2a mAb to the brain, and significantly reduced the plaque levels in the hippocampus followed by increased levels of synaptic proteins in synaptosomes, memory, and spatial learning in animals after three weeks. This finding demonstrated that FUS is a helpful tool to increase the efficacy and delivery of an anti-pGlu3 Aβ mAb for immunotherapy through an independent mechanism or an additive effect [107]. Pyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, toxic form of Aβ that is present in cerebral amyloid plaques and vascular deposits. In a study, FUS/MBs were used to deliver the Fc-competent murine anti-pGlu3 Aβ mAb, 07/2a across the BBB to improve Aβ removal and restore memory in aged AD model APP/PS1 mice. In comparison with control, mice treated with FUS-mediated mAb showed significantly better spatial learning and memory. In addition, the reduction of Aβ42 and pGlu3 Aβ hippocampal plaque and increasing of Iba-1+ microglia and Ly6G+ monocytes were observed in the hippocampi of AD mice [117].

In a study, using MRI-guided FUS, the intravenous administration of a much lower dose of anti-Aβ antibodies in transgenic mice resulted in significant plaque reduction 4 days post-treatment, confirming an effective drug for AD treatment [16].

5.2 Tau protein

Tau protein is a microtubules-associated protein (MAP), which is predominantly found in axons to stimulate microtubule polymerization [111,118]. Tau is associated with dementia and neurological disorders [111,119]. Karakastani et al. evaluated the effect of FUS at the early steps of Tau pathology (pre-tangle) in the rTg4510 mice model. The result demonstrated that the FUS reduced phosphorylated Tau in pyramidal CA1 neurons of the hippocampus without an enhancement in the phosphorylated Tau neuronal somas, which is usually associated with disease progression. It was also found that the FUS does not impair nerve integrity [108]. FUS can facilitate the transmission of antibody fragments against pathological Tau in transgenic tau P301L mice. The treatment of transgenic mice with repeated FUS for 15 weeks showed considerable reduction in Tau pathology without obvious histological damage, and improvement of memory and motor function. In addition, FUS promoted the autophagy pathway in neurons revealed through a decrease in the autophagic flux marker p62, reduction of mTOR activity, increase in beclin 1 level, and increase in the autophagosome membrane marker LC3II. The clearance of Tau by autophagy is reflected by a considerable increase in the interaction of p62 and Tau in the treatment group [109]. In a study, triple transgenic AD animals with Tau and Aβ deposits were treated by FUS in combination with MBs twice per week for 6 weeks. Considerable improvement in memory and learning ability, phosphorylated Tau, and Aβ deposits in the sonicated hemisphere were seen in the treated group [52].

6 Sonogenetics-based FUS/MBs approaches on the road to AD treatment

Sonogenetics is a combination of genetics and ultrasound-based methods to noninvasively control cell activity by stimulating the expression of ultrasound-sensitive proteins in the cell [[120], [121], [122]]. For this process, the gene encoding FUS-responsive proteins or other manipulated genes transfers to the preferred cells after the changes caused by ultrasound on the cell. FUS-based sonogenetics technique affects also cell function leading to significant changes in the biological process including differentiation, proliferation, and apoptosis [123]. It is noteworthy that in addition to the mechanical effect of FUS, a thermal effect arises from the motion of target molecules in response to ultrasound radiation, which is due to the increased internal energy of the molecule [120,123].

The genetic tools enable the precise expression of specific FUS-sensing proteins in various cells, providing target cells with enhanced FUS sensitivity compared to other cells [123,124]. sonogenetics targets specific neuronal populations through the use of sound waves activating genetically overexpressed mechanically or thermally sensitive ion channels [125].

Transient receptor potential (TRP) channels are one of the main targets in sonogenetics, whose genes can express at least 20 types of protein ion channels [126,127]. The TRP channels in mammalian tissues are involved in a diverse range of cellular and peripheral signals, allowing them to respond to a variety of chemical and physical stimuli and protect organs against harmful stimuli and acute conditions [128,129]. TRP channels have six transmembrane motifs that lead to the formation of non-selective cationic channels that act as signal transducer by changing membrane potential or intracellular calcium (Ca2+) [128,129].

One of the subfamilies of TRP channels is transient receptor potential vanilloid (TRPV) channels, which are divided into 5 subgroups (TPRV1-5) [130]. Among TPRV subtypes, the TRPV1 channel is commonly used in sonogenetics [123,131]. By the thermal effects of ultrasound waves to TRPV1 channels, the TRPV1 channel temperature reaches 42 °C resulting in calcium ions transportation from the outside of the cell membrane into the cells [120]. It can be surmised that TRP channels contribute to Aβ regulation [132]. Thus, the TRP channels can be a good candidate for sonogenetic FUS/MBs-based treatment of AD.

This technique may also be used as a tool to insert genes into neurons. Three genetic methods are used to insert the ultrasound-sensitive protein genes into the target cell genome, which is transfection, transmission through a suitable viral vector, and the applying transgenic animals. Although the BBB normally prevents the entry of viral vectors carrying manipulated genes to the brain cells, but FUS/MBs-induced approaches can facilitate this process. Gene therapy can make available the long-term accessibility of therapeutic agents in the brain through a single injection. The high transduction efficiency of a non-invasive gene-delivery system to the brain of an amyloidosis model across the BBB was revealed by the FUS combined with intravenous MBs and the recombinant adeno-associated virus (rAAV)-based capsid named rev-PHP.B [133]. In another same study, it was shown that the MRgFUS in combination with MBs could be increased the penetration and delivery of intravenously injected rAAV serotype 1/2 (rAAV1/2) to the hippocampus and cortex of the TgCRND8 mouse AD model hereby enhancing transgene expression in astrocytes surrounding amyloid plaques [134]. Regarding, the rAAV-based vector integrated with specific genes can use in FUS/MBs sonogenetics for the management of AD cells that are genetically regulated with ultrasound-sensitive ion channels (Fig. 6). In a study, the expression of mPrestin, a genetically modified ultrasensitive protein, in the dopaminergic neurons of the substantia nigra in PD mouse by using the 0.5 MHz localized and repeated FUS. The expression of mPrestin in dopaminergic neurons was continued for days after a single administration of the adeno-associated virus. FUS stimulation improved the dopaminergic neurodegeneration and reduced the PD symptoms of the mice [135]. This study suggests that this sonogenetics approach has a therapeutic perspective in other neurodegenerative diseases especially AD due to the changes in the dopaminergic system reported in AD patients with cognitive symptoms [136,137].Fig. 6 The sonogenetics neuromodulation based on integrated plasmid into an viral vector and FUS-sensitive ion channels [138].

Fig. 6

The FUS-based sonogenetics have the potential to control cellular signaling and/or the expression of specific genes. Xhima et al. reported that MRIgFUS/MBs effectively delivered TrkA agonist D3 to the basal forebrain, which led to the activation of TrkA-dependent signaling pathways in cholinergic neurons (BFCNs), reducing p75NTR activation, and enhanced cholinergic function, choline acetyltransferase (ChAT) activity and acetycholine (Ach) release in TgCRND8 mice [110].

The BRICHOS domain is a precursor protein related to dementia (Bri2), amyloid lung disease (proSP-C), and cancer. Studies have shown that the recombinant human Bri2 and proSP-C BRICHOS domains reduce Aβ neurotoxicity in animal models of AD through delay in Aβ formation. FUS combined with intravenous MBs were employed to enhance the brain delivery of Rh proSP-C and Bri2 BRICHOS a targeted opening of the BBB. MRI confirmed the BBB opening in the hippocampal region and enhanced delivery of proSP-C and Bri2 domains to the brain parenchyma without any signs of tissue damage [139]. One of the most promising effective targets for AD treatment is the brain-derived nerve growth factor (BDNF), but the crossing of this factor through the BBB is difficult due to its high molecular weight. Wang et al., studied the therapeutic effect of BDNF retrovirus (MpLXSN-BDNF)-loaded MBs in combination with FUS in the animal AD model. In order to open the BBB, low-frequency MRgFUS was used at the same time in the left hippocampus of animals. At the beginning and one month after the application, the effects of overexpression of BDNF on AD rats were investigated. The result exhibited an increase in signal intensity at the BBB disruption zone via MR images. The crossing times of the original platform through BBB were considerably also enhanced after FUS-induced treatment. The reduction of contents of ACh and the number of ChAT-positive neurons in the brain confirmed the BDNF delivery to the target site. It can be concluded that FUS combined with viral BDNF-loaded MBs can promote the overexpression of exogenous gene BDNF, and play a therapeutic role in the AD animal model [140].

In a study, the BBB treatments via FUS with systematically injected MBs could cause acute inflammatory response through transient upregulation of pro-inflammatory genes. MRgFUS was used to identify the leukocytes and their contribution to reducing Aβ pathology in the TgCRND8 AD model. Intravascular leukocyte activity, trans-endothelial migration, and aggregation of cells as acute inflammation indicators were revealed in this study. The results showed that in the hemisphere exposed to FUS, there were much higher levels of neutrophils than in the control and untreated hemispheres. No considerable neutrophil recruitment and neutrophil phagocytosis of Aβ plaques was seen in TgCRND8 mice in comparison with untreated controls. The results of this study show to some extent the inflammatory cellular aspect of FUS/MBs-based AD treatment [141]. It seems the acoustic cavitation arising from pulsed FUS (pFUS) combined with MBs can initiate an inflammatory response in animals. Accordingly, the probable long-term effects of SIR in the brain after single and six-week sonication were examined by MRI. The animal received bromodeoxyuridine (BrdU) to label the brain cells, before sonication. Ultrasound was used in 9 and 7 focal areas in the right hippocampus and the left cortex, respectively. The result showed pathological changes including cortical atrophy, multiple hypointense areas, astrogliosis, and a persistent BBB in the half of animals. The presence of metallophagocytic in the parenchyma, the high numbers of systemic infiltrating CD68+ macrophages along with BrdU+ cells, activated astrocytes, increased areas of microglia, and the hyper-phosphorylation of Tau protein were confirmed in the pFUS receiving animals [142].

This technique can be useful in the study and even treatment of neurological diseases such as PD or AD. It is hoped that soon we will see the development of sonogenetics tools to better identify the physiological mechanisms responsible for various behaviors, as well as the development of this method in the treatment of neurological diseases.

7 Safety of FUS-induced MBs-based AD drug delivery

Real-time safety monitoring is another challenge in the clinical usage of FUS-induced MBs drug delivery. The ultrasound levels that exceed MBs thresholds cause inertial cavitation, vascular rupture, permanent tissue damage, and potentially lethal intracranial hemorrhage [69,143]. Headache, numbness and tingling, imbalance, speech, swallowing or memory problems are some possible side effects of FUS/MBs [144]. One of the most common adverse effects of FUS/MBs is the formation of microhemorrhages in the brain, which are raised from the increasing FUS intensity and MB dose, and increased degree of BBB opening [85,145]. It is demonstrated that FUS/MBs-induced brain microhemorrhage often resolves and there are no effects on long-term cognition and neurological function, confirming the repeated FUS treatments without permanently damaging brain tissue [146]. Clinical trials indicate that the repetitive BBB opening by FUS/MBs may be an option for neuromodulation in near-future therapies [147].

A diverse set of FUS parameters influence on BBB disruption efficacy and safety outcomes: MBs, transducer frequency, peak-negative pressure, pulse characteristics, and the dosing of ultrasound applications [148,149]. By employing repeated low frequencies (1 Hz), exposure burst lengths (0.01–10 ms), and pressure amplitudes less than 1 MPa at 20–30 s duration time in FUS/MBs, the chances of permanent tissue damage are minimized [150]. FUS frequencies ranging from 28 kHz to 8 MHz have been used for application in animal models, while a maximum of 1.5 MHz has been suggested for the successful opening of BBB with minimal tissue damage [74]. In clinical trials, one of four FDA-approved clinical-grade ultrasound systems including Exablate model 4000 Type 2, NaviFUS®, NeuroAccess, and Sonocloud9 with customizable parameters are recommended [85]. A variety of experimental models (rodents, rabbits, sheep, pigs, non-human primates (NHPs)) and humans have been employed to monitor safety outcomes following ultrasound-mediated BBB disruption [149].

The rapid restoration of the BBB after treatment is important which is related to the safety of using the delivery method. The time of restoration depends on the size and volume of the therapeutic formulation being delivered. In a study, the effect of opening volume on BBB recovery time after treatment was evaluated. For this purpose, rats received bilateral FUS treatments one hemisphere was exposed to a single sonication and the contralateral received 4 overlapping foci. The contrast-enhanced T1-weighted MRI at 0, 6, and 24 h after treatment, confirmed the large cross-sectional region of the BBB opening via multi-point sonication compared to the single-point case. Six hours after treatment, the opened volumes in 9 of 10 hemispheres were closed and another location was reduced and closed in 24 h. Small morphologic changes were seen by histologic analysis. No signs of hemorrhage and edema were detected at 6 and 24 h by T2-weighted images. The results showed that the opening volume of the BBB was not directly related to the closing time. In addition, the safety of treatment was confirmed via MRI [151]. The restoration and safety of FUS combined with intravenously MBs process in BBB opening was also evaluated in Yorkshire pigs as a large animal model of AD. To monitor for tissue damage and BBB opening determination, an MRI was used. The animals underwent neurological tests during treatment (1–4 weeks) and were sacrificed at the end of the study for histopathological studies. No adverse event was seen by neurological testing through treatments. MRI showed restored BBB integrity one week after each session [152].

Neprilysin (NEP) can effectively degrade Aβ, but conventional methods to increase the concentration of this drug, such as the transmission of viral vector, represented some limitations including low gene transfer efficiency, immune responses, and secondary toxicity. Accordingly, a tractable and physical NEP gene-delivery system via FUS/MBs was designed for AD treatment. The introduction of human NEP as plasmid into the skeletal muscle of AD mice revealed outstanding reductions of Aβ in the brain after 30 days with improved performance. This approach displayed the safe and effective properties for ameliorating AD-like symptoms in APP/PS1 mice [153].

Lynch et al., appraised the effect of vasculotide (VT) to accelerate the recovery of the disrupted BBB after FUS applying in the TgCRND8 mice AD model. Animals received 250 ng, intraperitoneal VT every 48 h for 90 days. MRI confirmed BBB permeability following FUS with intravenously injected MBs. As predicted, faster restoration of the BBB was seen through VT treatment following FUS in a TgCRND8 animal. This study demonstrated that FUS may induce BBB permeability by affecting the ultra-harmonic pressure of MBs and accelerated BBB restoration in an animal model by VT, which indicates its potential clinical utility to stimulate plasticity, repair, and vascular health in AD [154]. Recently, the safety and efficacy of FUS-targeted MBs destruction in the delivery of MBs-loaded Aβ antibody and neural stem cells (NSCs) in the transgenic mice model of AD was investigated. The treated animals were exposed to diagnostic FUS for 5 min once a week for 4 times and then Aβ plaque deposition, cognitive and memory functions, as well as the expression of synaptophysin (SYN) and BDNF were evaluated. The combined delivery of NSCs and MBs-Aβ antibody by FUS-targeted MBs destruction improved spatial learning and memory function, the clearance of Aβ plaques, and BDNF expression in the treated group in comparison with the control group [155].

Since trials are commonly directed the regulatory approval to the advantages of therapeutics, safety receives limited attention. Despite this, safety has a crucial role in the carrying of therapeutic approaches from in vitro to clinic. In addition, most studies of FUS/MBs-induced drug delivery have been performed on rodents, which are differentiated from humans in their many physiological behaviors. Therefore, it is important to consider this treatment in large animals that have more in common with humans to reach a proper idea of the safety of the FUS/MBs process. Although the safety and the noninvasive FUS/MBs-mediated BBB opening in the hippocampus and cortex was indicated in sheep as AD model [156], the safety of FUS/MBs-induced AD drug delivery was recently claimed in the clinical trial studies.

Rezai et al., in an initial clinical trial study, evaluated the feasibility, reversibility, and safety of FUS-based disruption of BBB in the treatment of the entorhinal cortex and hippocampus in 6 patients with early AD. No neurological worsening or side effects and cognitive were observed during treatment. After FUS, a sizable and immediate enhancement in hippocampal parenchymal was confirmed by MRI indicating BBB opening as well as BBB closure within 24 h. The result of the present study exhibited noninvasively, safely, transiently, focally, and reproducibly of FUS/MBs technique in the permeability of BBB in the hippocampus/EC in humans [157]. The primary outcomes of proof-of-concept, prospective, single-arm, feasibility, safety, and non-randomized phase I clinical trial demonstrated that MRgFUS in combination with intravenous MBs administration procedure was reversible and feasible without any serious clinical or radiological side effects. In addition, in 8/10 treatments in five patients opening in the parieto-occipital-temporal was confirmed and in all cases, no side and uneventful effects were seen related to the BBB opening while a cognitive improvement was detected [158]. In an open-label, prospective clinical study, FUS-mediated BBB opening was performed on five patients in Korea, by targeting the bilateral frontal lobe regions twice at three-month intervals. The results confirmed BBB opening at 95 % of the targeted volume in the frontal lobe and a significant decrease in the standardized uptake value ratio 3 months later without adverse effects [159]. In a pilot clinical trial efficacy and safety of implantable FUS device in patients with mild AD was investigated. To target the left supramarginal gyrus, a 1 MHz ultrasound device was extradural implanted in the skull of 10 mild AD patients. Temporary disruption of BBB was carried out using 7 FUS sessions in combination with intravenous administration of MBs for 3.5 months. To monitor cognitive evaluations, amyloid levels, and brain metabolism, the positron emission tomography (PET)/MRI scan was applied 4 and 8 months after sonication. No significant changes in these factors in this study revealed the safety of FUS/MBs-induced therapy for AD patients. However, due to the duration and small sample size of the trial, a larger clinical trial is needed [160].

However, the intravenous injection of MBs has been shown to be safe compared to the use of conventional techniques such as MRI and radiography, but MBs destruction in the circulation of MBs in the bloodstream is also an important challenge. In FUS/MBs, several safety considerations for example the accurate targeting, the risk of tissue heating, and the ability to monitor in vivo MBs cavitation may be addressed.

Although stable cavitation of MBs at low-pressure FUS increases vascular permeability and drug penetration, excessive acoustic pressure causes rapid collapse of MB (inertial cavitation) leading to strong mechanical stresses, MB micro-jetting, and thermal effects in the vascular system [70,161]. These phenomena play a key role in the initiation of FUS-induced adverse effects during BBB opening [162].

The parameters of the ultrasound wave are another factors that influence the biological effects of MBs, so a detailed understanding of these can help the safe application of FUS/MBs in humans [70]. It is demonstrated that increasing acoustic pressure below a certain threshold, modulates the BBB opening, vascular leakage, and adverse effects on the blood vessels. It is now accepted that FUS at pressures at 0.2–1.0 MPa (220 kHz) can safely be applied in small cohort clinical studies [94]. Moreover, burst length, burst repetition frequency and sonication duration affect biological responses to FUS/MBs. The burst length between 0.1 and 10 ms, increasing burst repetition frequency from 0.1 Hz to 1 Hz, and decreasing 10-fold the sonication time at this frequency is able to BBB permeability enhancement [70].

The large temperature changes, generated by FUS, are undesirable due to the risk of causing damage to normal neural tissue. Therefore, the pulsed lower pressure intensity FUS that does not affect MB modulation is recommended. Short-time FUS hyperthermia can remarkably enhance the delivery of drugs to the mouse brain, without affecting uptake in normal, healthy brain tissues [163,164].

8 Experimental to clinical applications of FUS/MBs-assisted AD treatment

To date, the effect of FUS/MBs on the delivery of Aβ and tau therapeutics, behavioral impairments, inflammatory responses, and neuronal health have been investigated. In addition, In vitro, in vivo FUS/MBs-mediated BBB opening on animal models are well underway and has been used to deliver drugs, antibodies, NPs, and gene therapies for the treatment of AD in preclinical studies [74,124]. In this line, an in-depth understanding of the effect of FUS/MBs physical parameters on the biological performance of the human brain can promise the clinical application of FUS/MBs [70,147]. It is necessary to consider the interactions of MBs and the vasculature in the FUS field, ultrasound parameters (acoustic pressure, sonication duration, frequency, burst repetition frequency, burst length), chemical formulation, size distribution, and half-life of MBs [165]. Modification and standardization of protocols and parameters in future preclinical and clinical studies are required to inform robust clinical translation [74,165].

As FUS technology continues to advance, some challenges in the translatability of preclinical studies to clinical are necessary to be addressed. Treatment manner standardization, the novel therapeutic agent's efficacy, and the development of tools and models reflective of clinical conditions are some instances [85]. In this line, the human induced pluripotent stem cell (hiPSC) has been suggested that can be a novel in vitro model for the assessment of FUS/MBs-assisted anti-AD drug delivery, which provides a mimic model for clinical cases responses to FUS/MBs in the future [74].

9 Conclusion and future perspective

The high prevalence of AD and the related progressive challenges are critically evident that new medicine and treatment manner are required. The slow progress in AD therapy arose from BBB. FUS-induced approaches in combination with MBs are an innovative approach due to their advanced ability to penetrate the BBB.

The FUS-induced MBs-based drug delivery is a talented approach to reaching focal delivery of therapeutics including antibodies, NPs, and chemical drugs into the brain in a reversible process [16]. Although it is in the early phase, it has the potential to introduce precision medicine in treating AD patients. Although the above-mentioned FUS-induced MBs drug delivery strategies have shown significant efficacy, the brain delivery performance in some AD-induced animal models has not been quantitatively determined and needs to be further studied. Numerous studies have shown no serious side effects and no chemical or genetic changes in FUS-induced MBs for AD drug delivery. These findings have raised great hopes for the effective treatment of AD. However, despite the great motivation for applying this strategy, the underlying cellular and molecular mechanisms of ultrasonic neuronal modulation remain largely unknown [166,167]. Due to the presence of physical effects such as heating, cavities, and mechanical forces in ultrasound, the study of the mechanism is very important. In MBs-assisted FUS, the FUS frequency influences the penetrability. While, higher frequency FUS provides a limited penetrability, the lower frequency FUS offers excellent penetrability. In addition, low-intensity FUS can induce heating, mechanical forces, and cavitation. Variations in acoustic properties or the expression profiles of endogenous FUS-sensing proteins in different tissues can be affected by the bio-effects of FUS. The overexpression of heterogeneous FUS-sensing proteins is an approach to address this challenge due to the desired neuromodulation via FUS stimulation [124].

It is also hypothesized that the FUS/MBs combination can promote hippocampal neurogenesis, which is involved in memory and learning and is effective in neurological illnesses such as AD. In a study in adult mice, FUS/MBs mediated treatment remarkably could increase the proliferated cells number and newborn neurons in the hippocampal dentate gyrus [168]. In a cholinergic degeneration animal model of dementia, the improvement of spatial memory and hippocampal neurogenesis via FUS/MBs mechanisms was seen [169]. Despite this, it is not yet clear whether FUS can modulate this process in cholinergic deficiency conditions. FUS/MBs can induce BBB disruption in a wide range of brain regions with varying vasculature and structural properties, such as the hippocampus, striatum, and brainstem [170]. The hippocampus is strongly implicated in the pathology of dementia, offering an attractive drug target region in responses to the FUS/MBs [70]. A significantly increased AChE activity was observed in the hippocampus 18 days after FUS, which implies that the FUS-mediated BBB opening resulted in the recovery of AChE levels [169]. It has demonstrated transcriptional changes in hippocampal microvessels following FUS that are indicative of the initiation of angiogenic processes [171].

The FUS/MBs process involves a microbubble being loaded with a drug and conjugated with targeting moieties such as aptamers, peptides, and antibodies can represent a promising platform for the effective capture of AD biomarkers and specific delivery of therapeutic agents. Using this approach, the drugs can internalize to target cells via receptor-mediated delivery [172]. Regarding specific cell targeting for drug delivery, the functionalities can be used as surface functionalization of a biomaterial and target specific cell receptors. Once they bind to the cell receptor, for example receptor mediated endocytosis could occur, and the encapsulated drugs can be released in the lysosome. These functionalized biomaterials could be beneficial for delivering drugs, stimulating or inhibiting the cells, or for imaging and diagnostic purposes [173]. Aptamers could be beneficial in the intra-cellular delivery of therapeutics. They have high affinity and specificity in target recognition which remarkably enhances cellular uptake of aptamers and makes them very suitable for targeted drug delivery [174].

It should be noticed the modification of the MBs shell with the various component can critically influence their internalization into the target cell [175]. The surface functionalization can improve BBB penetration, target ability, and bioavailability of MBs. However, many concerns still need to be addressed, for instance, the accurate indication of the transition time, degree, location, and diversity of MBs crossing the BBB. Another factor that may influence the functionalized MBs emanates from their interaction with the plasma proteins resulting in the protein corona formation [176,177]. The interaction between nanoparticles with serum biomolecules such as proteins or lipids in biological fluids may form a layer of biomolecules around NPs, which is called the “protein corona” [178]. This phenomenon leads to changes in the physicochemical properties of NPs including size, shape, composition, and surface functionalization of the NPs, and subsequently affects their biomedical functionalities [178,179].

Most FUS-based drug delivery strategies must focus to targeting the pathophysiological factors of AD such as Aβ and tau. However, most studies that have confirmed acceptable results in preclinical studies may have failed in clinical trials, progress in FUS/MBs-based therapy in preclinical models of AD has revealed great potential to go beyond from in vitro to the clinic. In a study, the application of the MRgFUS was reported to five patients with AD. However, this study was performed on a small sample size and the efficiency to treat AD was not studied [94]. Further clinical data must be collected to confirm the application of FUS/MBs in humans. Therefore, future research using FUS/MBs-based delivery to the brain should attention to improving safety, precise targeting, and pharmacokinetic properties. In conclusion, it can be determined that FUS/MBs-based sonogenetics approaches have a notable therapeutic potential for AD. The application of nanoformulations will undoubtedly provide talented choices for the diagnosis and treatment of AD in the future. Among various drugs for AD, Aducanumab as an FDA-approved anti-Aβ monoclonal antibody for AD treatment can be an option for FUS/MBs that can effectively cure AD.

Availability of data and materials

Not applicable.

CRediT authorship contribution statement

Nadiyeh Rouhi: Writing – review & editing, Writing – original draft. Zahra Chakeri: Writing – original draft, Software. Behnam Ghorbani Nejad: Writing – original draft. Milad Rahimzadegan: Writing – review & editing. Mohammad Rafi Khezri: Writing – review & editing. Hossein Kamali: Writing – review & editing, Supervision. Rahim Nosrati: Writing – review & editing, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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References

1 Hussain R. Zubair H. Pursell S. Shahab M. Neurodegenerative diseases: regenerative mechanisms and novel therapeutic approaches Brain Sci. 8 2018 177 30223579
2 Hansson O. Biomarkers for neurodegenerative diseases Nat. Med. 27 2021 954 963 34083813
3 Mohammadpour F. Kamali H. Hadizadeh F. Bagheri M. Shiadeh S.N.R. Nazari A. Oroojalian F. Khodaverdi E. The PLGA microspheres synthesized by a thermosensitive hydrogel emulsifier for sustained release of risperidone J. Pharm. Innov. 17 2022 712 724 10.1007/s12247-021-09544-7
4 Sudhakar V. Richardson R.M. Gene therapy for neurodegenerative diseases Neurotherapeutics 16 2019 166 175 30542906
5 Agrawal M. Biswas A. Molecular diagnostics of neurodegenerative disorders Front. Mol. Biosci. 2 2015 54 26442283
6 Ramakrishna K. Nalla L.V. Naresh D. Venkateswarlu K. Viswanadh M.K. Nalluri B.N. Chakravarthy G. Duguluri S. Singh P. Rai S.N. Kumar A. Singh V. Singh S.K. WNT-Β catenin signaling as a potential therapeutic target for neurodegenerative diseases: current status and future perspective Diseases 11 2023 89 37489441
7 Graham W.V. Bonito-Oliva A. Sakmar T.P. Update on Alzheimer's disease therapy and prevention strategies Annu. Rev. Med. 68 2017 413 430 28099083
8 Fan L. Mao C. Hu X. Zhang S. Yang Z. Hu Z. Sun H. Fan Y. Dong Y. Yang J. New insights into the pathogenesis of Alzheimer's disease Front. Neurol. 2020 1312 31998208
9 Agarwal M. Alam M.R. Haider M.K. Malik M.Z. Kim D.-K. Alzheimer's disease: an overview of major hypotheses and therapeutic options in nanotechnology Nanomaterials 11 2020 59 33383712
10 Singh M. Agarwal V. Pancham P. Jindal D. Agarwal S. Rai S.N. Singh S.K. Gupta V. A Comprehensive Review and Androgen Deprivation Therapy and its Impact on Alzheimer's Disease Risk in Older Men with Prostate Cancer, Degenerative Neurological and Neuromuscular Disease vol. 14 2024 33 46 10.2147/dnnd.s445130
11 Fonseca-Santos B. Gremião M.P.D. Chorilli M. Nanotechnology-based drug delivery systems for the treatment of Alzheimer's disease Int. J. Nanomed. 10 2015 4981
12 Wen M.M. El-Salamouni N.S. El-Refaie W.M. Hazzah H.A. Ali M.M. Tosi G. Farid R.M. Blanco-Prieto M.J. Billa N. Hanafy A.S. Nanotechnology-based drug delivery systems for Alzheimer's disease management: technical, industrial, and clinical challenges J. Contr. Release 245 2017 95 107
13 Arya M.A. Manoj Kumar M.K. Sabitha M. Menon K.N. Nair S.C. Nanotechnology approaches for enhanced CNS delivery in treating Alzheimer's disease J. Drug Deliv. Sci. Technol. 51 2019 297 309 10.1016/j.jddst.2019.03.022
14 Teleanu D.M. Chircov C. Grumezescu A.M. Volceanov A. Teleanu R.I. Blood-brain delivery methods using nanotechnology Pharmaceutics 10 2018 269 30544966
15 Nazıroğlu M. Muhamad S. Pecze L. Nanoparticles as potential clinical therapeutic agents in Alzheimer's disease: focus on selenium nanoparticles Expet Rev. Clin. Pharmacol. 10 2017 773 782
16 Etame A.B. Diaz R.J. Smith C.A. Mainprize T.G. Hynynen K. Rutka J.T. Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology Neurosurg. Focus 32 2012 E3
17 Burgess A. Shah K. Hough O. Hynynen K. Focused ultrasound-mediated drug delivery through the blood–brain barrier Expert Rev. Neurother. 15 2015 477 491 25936845
18 Wu S.-K. Tsai C.-L. Huang Y. Hynynen K. Focused ultrasound and microbubbles-mediated drug delivery to brain tumor Pharmaceutics 13 2020 15 33374205
19 Liu Y. Gong Y. Xie W. Huang A. Yuan X. Zhou H. Zhu X. Chen X. Liu J. Liu J.J.N. Microbubbles in combination with focused ultrasound for the delivery of quercetin-modified sulfur nanoparticles through the blood brain barrier into the brain parenchyma and relief of endoplasmic reticulum stress to treat Alzheimer's disease Nanoscale 12 2020 6498 6511 32154811
20 Hernot S. Klibanov A.L. Microbubbles in ultrasound-triggered drug and gene delivery Adv. Drug Deliv. Rev. 60 2008 1153 1166 18486268
21 Bondi M.W. Edmonds E.C. Salmon D.P. Alzheimer's disease: past, present, and future J. Int. Neuropsychol. Soc. 23 2017 818 831 29198280
22 Rouhi N. Akhgari A. Orouji N. Nezami A. Rahimzadegan M. Kamali H. Recent progress in the graphene-based biosensing approaches for the detection of Alzheimer's biomarkers J. Pharm. Biomed. Anal. 222 2023 115084 10.1016/j.jpba.2022.115084
23 Fonseca L.C. Lopes J.A. Vieira J. Viegas C. Oliveira C.S. Hartmann R.P. Fonte P. Intranasal drug delivery for treatment of Alzheimer's disease Drug Delivery and Translational Research 11 2021 411 425 33638130
24 Tripathi P.N. Srivastava P. Sharma P. Tripathi M.K. Seth A. Tripathi A. Rai S.N. Singh S.P. Shrivastava S.K. Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory Bioorg. Chem. 85 2019 82 96 10.1016/j.bioorg.2018.12.017 30605887
25 Srivastava P. Tripathi P.N. Sharma P. Rai S.N. Singh S.P. Srivastava R.K. Shankar S. Shrivastava S.K. Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory Eur. J. Med. Chem. 163 2019 116 135 10.1016/j.ejmech.2018.11.049 30503937
26 Van Bulck M. Sierra-Magro A. Alarcon-Gil J. Perez-Castillo A. Morales-Garcia J.A. Novel approaches for the treatment of Alzheimer's and Parkinson's disease Int. J. Mol. Sci. 20 2019 719 30743990
27 Yiannopoulou K.G. Papageorgiou S.G. Current and future treatments in Alzheimer disease: an update J. Cent. Nerv. Syst. Dis. 12 2020 1179573520907397
28 Kingston A. Comas-Herrera A. Jagger C. Forecasting the care needs of the older population in England over the next 20 years: estimates from the Population Ageing and Care Simulation (PACSim) modelling study Lancet Public Health 3 2018 e447 e455 30174210
29 Barnabas W. Drug targeting strategies into the brain for treating neurological diseases J. Neurosci. Methods 311 2019 133 146 30336221
30 Fulop T. Witkowski J.M. Bourgade K. Khalil A. Zerif E. Larbi A. Hirokawa K. Pawelec G. Bocti C. Lacombe G. Can an infection hypothesis explain the beta amyloid hypothesis of Alzheimer's disease? Front. Aging Neurosci. 10 2018 224 30087609
31 Tripathi P.N. Lodhi A. Rai S.N. Nandi N.K. Dumoga S. Yadav P. Tiwari A.K. Singh S.K. El-Shorbagi A.A. Chaudhary S. Review of pharmacotherapeutic targets in alzheimer's disease and its management using traditional medicinal plants Degener. Neurol. Neuromuscul. Dis. 14 2024 47 74 10.2147/dnnd.s452009 38784601
32 Wang Y.-w. Zhou Q. Zhang X. Qian Q.-q. Xu J.-w. Ni P.-f. Qian Y.-n. Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization J. Neuroinflammation 14 2017 233 10.1186/s12974-017-1002-7 29179727
33 Rai S.N. Singh C. Singh A. Singh M.P. Singh B.K. Mitochondrial dysfunction: a potential therapeutic target to treat Alzheimer's disease Mol. Neurobiol. 57 2020 3075 3088 10.1007/s12035-020-01945-y 32462551
34 Poudel P. Park S. Recent advances in the treatment of Alzheimer's disease using nanoparticle-based drug delivery systems Pharmaceutics 14 2022 835 35456671
35 Cummings J. Lee G. Zhong K. Fonseca J. Taghva K. Alzheimer's disease drug development pipeline: 2021 Alzheimer's Dementia: Translational Research & Clinical Interventions 7 2021 e12179
36 Zhang M. Schmitt-Ulms G. Sato C. Xi Z. Zhang Y. Zhou Y. St George-Hyslop P. Rogaeva E. Drug repositioning for Alzheimer's disease based on systematic ‘omics’ data mining PLoS One 11 2016 e0168812
37 Cai Z. Qiao P.-F. Wan C.-Q. Cai M. Zhou N.-K. Li Q. Role of blood-brain barrier in Alzheimer's disease J. Alzheim. Dis. 63 2018 1223 1234
38 Wong K.H. Riaz M.K. Xie Y. Zhang X. Liu Q. Chen H. Bian Z. Chen X. Lu A. Yang Z. Review of current strategies for delivering Alzheimer's disease drugs across the blood-brain barrier Int. J. Mol. Sci. 20 2019 381 30658419
39 Gorain B. Rajeswary D.C. Pandey M. Kesharwani P. Kumbhar S.A. Choudhury H. Nose to brain delivery of nanocarriers towards attenuation of demented condition Curr. Pharm. Des. 26 2020 2233 2246 32167424
40 Geis N.A. Katus H.A. Bekeredjian R. Microbubbles as a vehicle for gene and drug delivery: current clinical implications and future perspectives Curr. Pharm. Des. 18 2012 2166 2183 22352771
41 Wu D. Chen Q. Chen X. Han F. Chen Z. Wang Y. The blood–brain barrier: structure, regulation, and drug delivery Signal Transduct. Targeted Ther. 8 2023 217 10.1038/s41392-023-01481-w
42 Pardridge W.M. Drug transport across the blood-brain barrier J. Cereb. Blood Flow Metab. 32 2012 1959 1972 10.1038/jcbfm.2012.126 22929442
43 Chen Y. He Y. Han J. Wei W. Chen F. Blood-brain barrier dysfunction and Alzheimer's disease: associations, pathogenic mechanisms, and therapeutic potential Front. Aging Neurosci. 15 2023 1258640 10.3389/fnagi.2023.1258640
44 Zenaro E. Piacentino G. Constantin G. The blood-brain barrier in Alzheimer's disease Neurobiol. Dis. 107 2017 41 56 10.1016/j.nbd.2016.07.007 27425887
45 Kurz C. Walker L. Rauchmann B.-S. Perneczky R. Dysfunction of the blood–brain barrier in Alzheimer's disease: evidence from human studies Neuropathol. Appl. Neurobiol. 48 2022 e12782 10.1111/nan.12782
46 Sirsi S.R. Borden M.A. Microbubble compositions, properties and biomedical applications Bubble Sci. Eng. Technol. 1 2009 3 17 20574549
47 Zhang Y. Yu J. Bomba H.N. Zhu Y. Gu Z. Mechanical force-triggered drug delivery Chem. Rev. 116 2016 12536 12563 27680291
48 Wang S. Samiotaki G. Olumolade O. Feshitan J.A. Konofagou E.E. Microbubble type and distribution dependence of focused ultrasound-induced blood–brain barrier opening Ultrasound Med. Biol. 40 2014 130 137 10.1016/j.ultrasmedbio.2013.09.015 24239362
49 Li H. Wang J. Huang G. Wang P. Zheng R. Zhang C. Jiang Q. Multifunctionalized microbubbles for cancer diagnosis and therapy Anti Cancer Agents Med. Chem. 13 2013 403 413
50 Lapin N.A. Gill K. Shah B.R. Chopra R. Consistent opening of the blood brain barrier using focused ultrasound with constant intravenous infusion of microbubble agent Sci. Rep. 10 2020 16546 10.1038/s41598-020-73312-9
51 Martin K.H. Dayton P.A. Current status and prospects for microbubbles in ultrasound theranostics Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 5 2013 329 345 23504911
52 Shen Y. Hua L. Yeh C.-K. Shen L. Ying M. Zhang Z. Liu G. Li S. Chen S. Chen X.J.T. Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer's disease Theranostics 10 2020 11794
53 Zhao Y.-Z. Du L.-N. Lu C.-T. Jin Y.-G. Ge S.-P. Potential and problems in ultrasound-responsive drug delivery systems Int. J. Nanomed. 8 2013 1621
54 McMahon D. Hynynen K. Acute inflammatory response following increased blood-brain barrier permeability induced by focused ultrasound is dependent on microbubble dose Theranostics 7 2017 3989 29109793
55 Endo-Takahashi Y. Negishi Y. Microbubbles and nanobubbles with ultrasound for systemic gene delivery Pharmaceutics 12 2020 964 33066531
56 Bukari B. Samarasinghe R.M. Noibanchong J. Shigdar S.L. Non-invasive delivery of therapeutics into the brain: the potential of aptamers for targeted delivery Biomedicines 8 2020 120 32422973
57 Raliya R. Saha D. Chadha T.S. Raman B. Biswas P. Non-invasive aerosol delivery and transport of gold nanoparticles to the brain Sci. Rep. 7 2017 44718 10.1038/srep44718
58 Bellotti E. Schilling A.L. Little S.R. Decuzzi P. Injectable thermoresponsive hydrogels as drug delivery system for the treatment of central nervous system disorders: a review J. Contr. Release 329 2021 16 35
59 Parkin Beth L. Ekhtiari H. Walsh Vincent F. Non-invasive human brain stimulation in cognitive neuroscience: a primer Neuron 87 2015 932 945 10.1016/j.neuron.2015.07.032 26335641
60 Fini M. Tyler W.J. Transcranial focused ultrasound: a new tool for non-invasive neuromodulation Int. Rev. Psychiatr. 29 2017 168 177
61 Wagner T. Valero-Cabre A. Pascual-Leone A. Noninvasive human brain stimulation Annu. Rev. Biomed. Eng. 9 2007 527 565 17444810
62 Tu L. Liao Z. Luo Z. Wu Y.L. Herrmann A. Huo S. Ultrasound‐controlled drug release and drug activation for cancer therapy Explorations 1 2021 20210023
63 Ho Y.-J. Huang C.-C. Fan C.-H. Liu H.-L. Yeh C.-K. Ultrasonic technologies in imaging and drug delivery, Cell Mol. Life Sci. 78 2021 6119 6141
64 Yoo S. Mittelstein D.R. Hurt R.C. Lacroix J. Shapiro M.G. Focused ultrasound excites cortical neurons via mechanosensitive calcium accumulation and ion channel amplification Nat. Commun. 13 2022 1 13 34983933
65 Maresca D. Lakshmanan A. Abedi M. Bar-Zion A. Farhadi A. Lu G.J. Szablowski J.O. Wu D. Yoo S. Shapiro M.G. Biomolecular ultrasound and sonogenetics Annu. Rev. Chem. Biomol. Eng. 9 2018 229 252 29579400
66 Zhou Y. Huo S. Loznik M. Göstl R. Boersma A.J. Herrmann A. Controlling optical and catalytic activity of genetically engineered proteins by ultrasound Angew. Chem. Int. Ed. 60 2021 1493 1497
67 Deng C.X. Targeted drug delivery across the blood–brain barrier using ultrasound technique Ther. Deliv. 1 2010 819 848 21785679
68 Bakhtiari-Nejad M. Shahab S. Effects of nonlinear propagation of focused ultrasound on the stable cavitation of a single bubble Acoustics 2018 MDPI 14 34
69 Appelboom G. Detappe A. LoPresti M. Kunjachan S. Mitrasinovic S. Goldman S. Chang S.D. Tillement O. Stereotactic modulation of blood-brain barrier permeability to enhance drug delivery Neuro Oncol. 18 2016 1601 1609 27407134
70 Wasielewska J.M. White A.R. Focused ultrasound-mediated drug delivery in humans - a path towards translation in neurodegenerative diseases Pharm. Res. (N. Y.) 39 2022 427 439 10.1007/s11095-022-03185-2
71 Ting C.-Y. Fan C.-H. Liu H.-L. Huang C.-Y. Hsieh H.-Y. Yen T.-C. Wei K.-C. Yeh C.-K. Concurrent blood–brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment Biomaterials 33 2012 704 712 10.1016/j.biomaterials.2011.09.096 22019122
72 Olsman M. Sereti V. Mühlenpfordt M. Johnsen K.B. Andresen T.L. Urquhart A.J. de Lange Davies C. Focused ultrasound and microbubble treatment increases delivery of transferrin receptor-targeting liposomes to the brain Ultrasound Med. Biol. 47 2021 1343 1355 33608142
73 Åslund A.K.O. Berg S. Hak S. Mørch Ý. Torp S.H. Sandvig A. Widerøe M. Hansen R. de Lange Davies C. Nanoparticle delivery to the brain — by focused ultrasound and self-assembled nanoparticle-stabilized microbubbles J. Contr. Release 220 2015 287 294 10.1016/j.jconrel.2015.10.047
74 Wasielewska J.M. White A.R. Focused ultrasound-mediated drug delivery in humans–a path towards translation in neurodegenerative diseases Pharm. Res. (N. Y.) 39 2022 427 439
75 Meng Y. Pople C.B. Lea-Banks H. Abrahao A. Davidson B. Suppiah S. Vecchio L.M. Samuel N. Mahmud F. Hynynen K. Hamani C. Lipsman N. Safety and efficacy of focused ultrasound induced blood-brain barrier opening, an integrative review of animal and human studies J. Contr. Release 309 2019 25 36 10.1016/j.jconrel.2019.07.023
76 Wu J. Nyborg W.L. Ultrasound, cavitation bubbles and their interaction with cells Adv. Drug Deliv. Rev. 60 2008 1103 1116 18468716
77 Sboros V. Response of contrast agents to ultrasound Adv. Drug Deliv. Rev. 60 2008 1117 1136 18486270
78 Samiotaki G. Karakatsani M.E. Buch A. Papadopoulos S. Wu S.Y. Jambawalikar S. Konofagou E.E. Pharmacokinetic analysis and drug delivery efficiency of the focused ultrasound-induced blood-brain barrier opening in non-human primates Magn. Reson. Imaging 37 2017 273 281 10.1016/j.mri.2016.11.023 27916657
79 Belgamwar V.S. Bhoyar V.T. Trivedi S. Pardeshi C.V. Chapter 23 - quantitative and qualitative analysis of direct nose-to-brain drug delivery Pardeshi C.V. Souto E.B. Direct Nose-To-Brain Drug Delivery 2021 Academic Press 459 481
80 Kozlovskaya L. Stepensky D. Quantitative analysis of the brain-targeted delivery of drugs and model compounds using nano-delivery systems J. Contr. Release 171 2013 17 23 10.1016/j.jconrel.2013.06.028
81 McMahon D. Poon C. Hynynen K. Evaluating the safety profile of focused ultrasound and microbubble-mediated treatments to increase blood-brain barrier permeability Expet Opin. Drug Deliv. 16 2019 129 142
82 Liang X. Xu Y. Gao C. Zhou Y. Zhang N. Dai Z. Ultrasound contrast agent microbubbles with ultrahigh loading capacity of camptothecin and floxuridine for enhancing tumor accumulation and combined chemotherapeutic efficacy NPG Asia Mater. 10 2018 761 774
83 Hameed S. Zhang M. Bhattarai P. Mustafa G. Dai Z. Enhancing cancer therapeutic efficacy through ultrasound‐mediated micro‐to‐nano conversion Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 12 2020 e1604
84 Tung Y.-S. Marquet F. Teichert T. Ferrera V. Konofagou E.E. Bubble dependence of the mechanism of FUS-induced blood-brain barrier opening in mice and in monkeys in vivo 2011 IEEE International Ultrasonics Symposium, IEEE 2011 1898 1901
85 Seas A.A. Malla A.P. Sharifai N. Winkles J.A. Woodworth G.F. Anastasiadis P. Microbubble-enhanced focused ultrasound for infiltrating gliomas Biomedicines 12 2024 1230 38927437
86 Omata D. Maruyama T. Unga J. Hagiwara F. Munakata L. Kageyama S. Shima T. Suzuki Y. Maruyama K. Suzuki R. Effects of encapsulated gas on stability of lipid-based microbubbles and ultrasound-triggered drug delivery J. Contr. Release 311–312 2019 65 73 10.1016/j.jconrel.2019.08.023
87 Chang K.W. Hong S.W. Chang W.S. Jung H.H. Chang J.W. Characteristics of focused ultrasound mediated blood-brain barrier opening in magnetic resonance images J. Korean Neurosurg. Soc. 66 2023 172 182 36537034
88 Navarro-Becerra J.A. Borden M.A. Targeted microbubbles for drug, gene, and cell delivery in therapy and immunotherapy Pharmaceutics 15 2023 1625 37376072
89 Jangjou A. Meisami A.H. Jamali K. Niakan M.H. Abbasi M. Shafiee M. Salehi M. Hosseinzadeh A. Amani A.M. Vaez B.S. The promising shadow of microbubble over medical sciences: from fighting wide scope of prevalence disease to cancer eradication J. Biomed. Sci. 28 2021 1 24 33388061
90 Choi J.J. Feshitan J.A. Baseri B. Wang S. Tung Y.-S. Borden M.A. Konofagou E.E. Microbubble-size dependence of focused ultrasound-induced blood–brain barrier opening in mice in vivo ITBE 57 2009 145 154
91 Cheng B. Bing C. Xi Y. Shah B. Exner A.A. Chopra R. Influence of nanobubble concentration on blood–brain barrier opening using focused ultrasound under real-time acoustic feedback control Ultrasound Med. Biol. 45 2019 2174 2187 31072657
92 Choi J.J. Wang S. Brown T.R. Small S.A. Duff K.E. Konofagou E.E.J.U.i. Noninvasive and transient blood-brain barrier opening in the hippocampus of Alzheimer's double transgenic mice using focused ultrasound UltIm 30 2008 189 200
93 Santin M.D. Debeir T. Bridal S.L. Rooney T. Dhenain M.J.N. Fast in vivo imaging of amyloid plaques using μ-MRI Gd-staining combined with ultrasound-induced blood–brain barrier opening Neuroimage 79 2013 288 294 23660031
94 Lipsman N. Meng Y. Bethune A.J. Huang Y. Lam B. Masellis M. Herrmann N. Heyn C. Aubert I. Boutet A. Blood–brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound Nat. Commun. 9 2018 1 8 29317637
95 Raymond S.B. Treat L.H. Dewey J.D. McDannold N.J. Hynynen K. Bacskai B.J. Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models PLoS One 3 2008 e2175
96 Mohapatra D. Jena S. Prusty S. Sahu P. Biomarkers of alzheimer's disease: a review Syst. Rev. Pharm. 11 2020
97 El Kadmiri N. Said N. Slassi I. El Moutawakil B. Nadifi S. Biomarkers for alzheimer disease: classical and novel candidates' review Neuroscience 370 2018 181 190 10.1016/j.neuroscience.2017.07.017 28729061
98 Nance E. Timbie K. Miller G.W. Song J. Louttit C. Klibanov A.L. Shih T.-Y. Swaminathan G. Tamargo R.J. Woodworth G.F.J.J.o.c.r. Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood− brain barrier using MRI-guided focused ultrasound J. Contr. Release 189 2014 123 132
99 Deng Z. Wang J. Xiao Y. Li F. Niu L. Liu X. Meng L. Zheng H.J.T. Ultrasound-mediated augmented exosome release from astrocytes alleviates amyloid-β-induced neurotoxicity Theranostics 11 2021 4351 33754065
100 Hsu P.-H. Lin Y.-T. Chung Y.-H. Lin K.-J. Yang L.-Y. Yen T.-C. Liu H.-L. Focused ultrasound-induced blood-brain barrier opening enhances GSK-3 inhibitor delivery for amyloid-beta plaque reduction Sci. Rep. 8 2018 12882 10.1038/s41598-018-31071-8
101 Jordão J.F. Ayala‐Grosso C.A. Chopra R. McLaurin J. Aubert I. Hynynen K. Ultrasound delivery of an anti‐aβ therapeutic agent to the brain in a mouse model of Alzheimer's disease AIP Conf. Proc. 2009 American Institute of Physics 428 432
102 Alecou T. Giannakou M. Damianou C. Amyloid β plaque reduction with antibodies crossing the blood‐brain barrier, which was opened in 3 sessions of focused ultrasound in a rabbit model J. Ultrasound Med. 36 2017 2257 2270 28543446
103 Liu M. Jevtic S. Markham-Coultes K. Ellens N.P.K. O'Reilly M.A. Hynynen K. Aubert I. McLaurin J. Investigating the efficacy of a combination Aβ-targeted treatment in a mouse model of Alzheimer's disease Brain Res. 1678 2018 138 145 29066368
104 Dubey S. Heinen S. Krantic S. McLaurin J. Branch D.R. Hynynen K. Aubert N.A.o.S. Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease Proc. Natl. Acad. Sci. USA 117 2020 32691 32700 33288687
105 Leinenga G. Koh W.K. Götz J.J.A.s.r. therapy, A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease Alzheimer's Res. Ther. 13 2021 1 14 33397495
106 Bathini P. Sun T. Shi Q. Zhang Y. Taudte N. Schenk M. Hettmann T. Schilling S. McDannold N. Lemere C.A.J.A.s. Dementia, Focus Ultrasound‐Induced Blood‐Brain Barrier opening enhances anti‐pGlu3 Aβ mAb delivery and amyloid‐beta plaque clearance Alzheimer's Dementia 17 2021 e058725
107 Sun T. Shi Q. Zhang Y. Power C. Hoesch C. Antonelli S. Schroeder M.K. Caldarone B.J. Taudte N. Schenk o.C.R. Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells J. Contr. Release 336 2021 443 456
108 Karakatsani M.E. Kugelman T. Ji R. Murillo M. Wang S. Niimi Y. Small S.A. Duff K.E. Konofagou E.E.J.T. Unilateral focused ultrasound-induced blood-brain barrier opening reduces phosphorylated tau from the rTg4510 mouse model Theranostics 9 2019 5396 31410223
109 Pandit R. Leinenga G. Götz J.J.T. Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions Theranostics 9 2019 3754 31281511
110 Xhima K. Markham-Coultes K. Nedev H. Heinen S. Saragovi H.U. Hynynen K. Aubert I. Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer's disease Sci. Adv. 6 2020 eaax6646
111 Shui B. Tao D. Florea A. Cheng J. Zhao Q. Gu Y. Li W. Jaffrezic-Renault N. Mei Y. Guo Z. Biosensors for Alzheimer's disease biomarker detection: a review Biochimie 147 2018 13 24 10.1016/j.biochi.2017.12.015 29307704
112 Ma C. Su J. Sun Y. Feng Y. Shen N. Li B. Liang Y. Yang X. Wu H. Zhang H. Significant upregulation of alzheimer's β‐amyloid levels in a living system induced by extracellular elastin polypeptides Angew. Chem. 131 2019 18876 18882
113 Lee Y. Choi Y. Park E.-J. Kwon S. Kim H. Lee J.Y. Lee D.S.J.S.r. Improvement of glymphatic–lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer's disease model Sci. Rep. 10 2020 1 14 31913322
114 Ogawa K. Kato N. Yoshida M. Hiu T. Matsuo T. Mizukami S. Omata D. Suzuki R. Maruyama K. Mukai H. Kawakami S. Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain J. Contr. Release 348 2022 34 41 10.1016/j.jconrel.2022.05.042
115 van Dyck C.H. Anti-Amyloid-β monoclonal antibodies for alzheimer's disease: pitfalls and promise Biol. Psychiatry 83 2018 311 319 10.1016/j.biopsych.2017.08.010 28967385
116 Shi M. Chu F. Zhu F. Zhu J. Impact of anti-amyloid-β monoclonal antibodies on the pathology and clinical profile of Alzheimer's disease: a focus on aducanumab and lecanemab Front. Aging Neurosci. 14 2022 870517
117 Shi Q. Sun T. Zhang Y. Power C. Hoesch C. Antonelli S. Schroeder M.K. Caldarone B.J. Taudte N. Schenk M. Ultrasound-mediated blood-brain barrier disruption improves anti-pyroglutamate 3 Aβ antibody efficacy and enhances phagocyte infiltration into brain in aged Alzheimer’s disease-like mice bioRxiv 2021
118 Wang Y. Mandelkow E. Tau in physiology and pathology Nat. Rev. Neurosci. 17 2016 22 35 10.1038/nrn.2015.1 26656254
119 Scarano S. Lisi S. Ravelet C. Peyrin E. Minunni M. Detecting Alzheimer's disease biomarkers: from antibodies to new bio-mimetic receptors and their application to established and emerging bioanalytical platforms – a critical review Anal. Chim. Acta 940 2016 21 37 10.1016/j.aca.2016.08.008 27662756
120 Yang Y. Pacia C.P. Ye D. Zhu L. Baek H. Yue Y. Yuan J. Miller M.J. Cui J. Culver J.P. Sonogenetics for noninvasive and cellular-level neuromodulation in rodent brain bioRxiv 2020
121 Hou X. Qiu Z. Kala S. Guo J. Wong K.F. Zhu T. Zhu J. Xian Q. Yang M. Sun L. Ultrasound neuromodulation through nanobubble-actuated sonogenetics bioRxiv 2020 2020–10
122 Athanassiadis A.G. Ma Z. Moreno-Gomez N. Melde K. Choi E. Goyal R. Fischer P. Ultrasound-responsive systems as components for smart materials Chem. Rev. 122 2021 5165 5208 34767350
123 Azadeh S.S. Lordifard P. Soheilifar M.H. Djavid G.E. Neghab H.K. Ultrasound and sonogenetics: a new perspective for controlling cells with sound Iran. J. Pharm. Res. (IJPR): IJPR 20 2021 151 34903978
124 Wang H.-C. Phan T.-N. Kao C.-L. Yeh C.-K. Lin Y.-C. Genetically encoded mediators for sonogenetics and their applications in neuromodulation Front. Cell. Neurosci. 17 2023 1326279
125 Liu T. Choi M.H. Zhu J. Zhu T. Yang J. Li N. Chen Z. Xian Q. Hou X. He D. Guo J. Fei C. Sun L. Qiu Z. Sonogenetics: recent advances and future directions Brain Stimul. 15 2022 1308 1317 10.1016/j.brs.2022.09.002 36130679
126 Duque M. Lee-Kubli C.A. Tufail Y. Magaram U. Patel J. Chakraborty A. Mendoza Lopez J. Edsinger E. Vasan A. Shiao R. Sonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels Nat. Commun. 13 2022 1 17 34983933
127 Hong F. Li Y. Application of mechanosensitive channels in sonogenetics J. Zhejiang Univ. 48 2019 34 38
128 Zhao Y. McVeigh B.M. Moiseenkova-Bell V.Y. Structural pharmacology of TRP channels JMBio 433 2021 166914 10.1016/j.jmb.2021.166914
129 Samanta A. Hughes T.E.T. Moiseenkova-Bell V.Y. Transient receptor potential (TRP) channels Membrane Protein Complexes: Structure and Function 2018 141 165
130 Chinigò G. Castel H. Chever O. Gkika D. TRP Channels in brain tumors Front. Cell Dev. Biol. 9 2021
131 Wang S. Meng W. Ren Z. Li B. Zhu T. Chen H. Wang Z. He B. Zhao D. Jiang H. Ultrasonic neuromodulation and sonogenetics: a new era for neural modulation Front. Physiol. 11 2020 787 32765294
132 Yamamoto S. Wajima T. Hara Y. Nishida M. Mori Y. Transient receptor potential channels in Alzheimer's disease Biochim. Biophys. Acta (BBA) - Mol. Basis Dis. 1772 2007 958 967 10.1016/j.bbadis.2007.03.006
133 Kofoed R.H. Heinen S. Silburt J. Dubey S. Dibia C.L. Maes M. Simpson E.M. Hynynen K. Aubert I.J.M.T.-M. Development C. Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP. B to the brain in a mouse model of amyloidosis Molecular Therapy-Methods & Clinical Development 23 2021 390 405 34761053
134 Weber-Adrian D. Kofoed R.H. Chan J.W.Y. Silburt J. Noroozian Z. Kügler S. Hynynen K. Aubert I.J.T. Strategy to enhance transgene expression in proximity of amyloid plaques in a mouse model of Alzheimer's disease Theranostics 9 2019 8127 31754385
135 Fan C.-H. Wei K.-C. Chiu N.-H. Liao E.-C. Wang H.-C. Wu R.-Y. Ho Y.-J. Chan H.-L. Wang T.-S.A. Huang Y.-Z. Hsieh T.-H. Lin C.-H. Lin Y.-C. Yeh C.-K. Sonogenetic-based neuromodulation for the amelioration of Parkinson's disease Nano Lett. 21 2021 5967 5976 10.1021/acs.nanolett.1c00886 34264082
136 Nobili A. Latagliata E.C. Viscomi M.T. Cavallucci V. Cutuli D. Giacovazzo G. Krashia P. Rizzo F.R. Marino R. Federici M. De Bartolo P. Aversa D. Dell'Acqua M.C. Cordella A. Sancandi M. Keller F. Petrosini L. Puglisi-Allegra S. Mercuri N.B. Coccurello R. Berretta N. D'Amelio M. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease Nat. Commun. 8 2017 14727 10.1038/ncomms14727
137 Krashia P. Nobili A. D'Amelio M. Unifying hypothesis of dopamine neuron loss in neurodegenerative diseases: focusing on Alzheimer's disease Front. Mol. Neurosci. 12 2019 123 31156387
138 Xian Q. Qiu Z. Kala S. Guo J. Zhu J. Wong K.F. Guo S.S.Y. Zhu T. Hou X. Sun L. Protocol for the sonogenetic stimulation of mouse brain by non-invasive ultrasound STAR Protocols 2 2021 100393 10.1016/j.xpro.2021.100393
139 Galan-Acosta L. Sierra C. Leppert A. Pouliopoulos A. Kwon N. Noel R. Tambaro S. Presto J. Nilsson P. Konofagou E.J.M. Neuroscience C. Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons Mol. Cell. Neurosci. 105 2020 103498
140 Wang F. Wei X.-X. Chang L.-S. Dong L. Wang Y.-L. Li F.i.P. Ultrasound combined with microbubbles loading BDNF retrovirus to open blood–brain barrier for treatment of Alzheimer's disease Front. Pharmacol. 12 2021 36
141 Poon C. Pellow C. Hynynen K.J.F. Neutrophil recruitment and leukocyte response following focused ultrasound and microbubble mediated blood-brain barrier treatments Theranostics 20 2022 100 116
142 Kovacs Z.I. Tu T.-W. Sundby M. Qureshi F. Lewis B.K. Jikaria N. Burks S.R. Frank J.A.J.T. MRI and histological evaluation of pulsed focused ultrasound and microbubbles treatment effects in the brain Theranostics 8 2018 4837 30279741
143 Xu Z. Carlson C. Snell J. Eames M. Hananel A. Lopes M.B. Raghavan P. Lee C.-C. Yen C.-P. Schlesinger D. Intracranial inertial cavitation threshold and thermal ablation lesion creation using MRI-guided 220-kHz focused ultrasound surgery: preclinical investigation J. Neurosurg. 122 2015 152 161 25380106
144 Abe K. Taira T. Focused ultrasound treatment, present and future Neurol. Med.-Chir. 57 2017 386 391
145 Liu H.-L. Wai Y.-Y. Chen W.-S. Chen J.-C. Hsu P.-H. Wu X.-Y. Huang W.-C. Yen T.-C. Wang J.-J. Hemorrhage detection during focused-ultrasound induced blood-brain-barrier opening by using susceptibility-weighted magnetic resonance imaging Ultrasound Med. Biol. 34 2008 598 606 18313204
146 Kobus T. Vykhodtseva N. Pilatou M. Zhang Y. McDannold N. Safety validation of repeated blood–brain barrier disruption using focused ultrasound Ultrasound Med. Biol. 42 2016 481 492 26617243
147 Gorick C.M. Breza V.R. Nowak K.M. Cheng V.W.T. Fisher D.G. Debski A.C. Hoch M.R. Demir Z.E.F. Tran N.M. Schwartz M.R. Sheybani N.D. Price R.J. Applications of focused ultrasound-mediated blood-brain barrier opening Adv. Drug Deliv. Rev. 191 2022 114583 10.1016/j.addr.2022.114583
148 McDannold N. Vykhodtseva N. Hynynen K. Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index Ultrasound Med. Biol. 34 2008 834 840 18207311
149 Gandhi K. Barzegar-Fallah A. Banstola A. Rizwan S.B. Reynolds J.N. Ultrasound-mediated blood–brain barrier disruption for drug delivery: a systematic review of protocols, efficacy, and safety outcomes from preclinical and clinical studies Pharmaceutics 14 2022 833 35456667
150 Hynynen K. Ultrasound for drug and gene delivery to the brain Adv. Drug Deliv. Rev. 60 2008 1209 1217 18486271
151 O'Reilly M.A. Hough O. Hynynen U.i.M. Blood‐brain barrier closure time after controlled ultrasound‐induced opening is independent of opening volume J. Ultrasound Med. 36 2017 475 483 28108988
152 Jones R. Repeated hippocampal blood-brain barrier opening controlled via three-dimensional transcranial acoustic imaging: safety study in a porcine model IEEE International Ultrasonics Symposium 2017
153 Li Y. Wang Y. Wang J. Chong K.Y. Xu J. Liu Z. Shan C.J.M.T.-M. Development C. Expression of Neprilysin in Skeletal Muscle by Ultrasound-Mediated Gene Transfer (Sonoporation) Reduces Amyloid Burden for AD vol. 17 2020 300 308
154 Lynch M. Heinen S. Markham-Coultes K. O'Reilly M. Van Slyke P. Dumont D.J. Hynynen K. Aubert I.J.I.j.o.m.s. Vasculotide restores the blood-brain barrier after focused ultrasound-induced permeability in a mouse model of Alzheimer's disease Int. J. Med. Sci. 18 2021 482 33390817
155 Zhu Q. Xu X. Chen B. Liao Y. Guan X. He Y. Cui H. Rong Y. Liu Z. Xu Y.J.M.P. Ultrasound‐targeted microbubbles destruction assists dual delivery of beta‐amyloid antibody and neural stem cells to restore neural function in transgenic mice of Alzheimer's disease MedPh 49 2022 1357 1367
156 Pelekanos M. Leinenga G. Odabaee M. Odabaee M. Saifzadeh S. Steck R. Götz J.J.T. Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions Theranostics 8 2018 2583 29721100
157 Rezai A.R. Ranjan M. D'Haese P.-F. Haut M.W. Carpenter J. Najib U. Mehta R.I. Chazen J.L. Zibly Z. Yates N.A.o.S. Noninvasive hippocampal blood− brain barrier opening in Alzheimer's disease with focused ultrasound Proc. Natl. Acad. Sci. USA 117 2020 9180 9182 32284421
158 Gasca-Salas C. Fernández-Rodríguez B. Pineda-Pardo J.A. Rodríguez-Rojas R. Obeso I. Hernández-Fernández F. Del Álamo M. Mata D. Guida P. Ordás-Bandera C.J.N.c. Blood-brain barrier opening with focused ultrasound in Parkinson's disease dementia Nat. Commun. 12 2021 1 7 33397941
159 Park S.H. Baik K. Jeon S. Chang W.S. Ye B.S. Chang J.W. Extensive frontal focused ultrasound mediated blood–brain barrier opening for the treatment of Alzheimer's disease: a proof-of-concept study Transl. Neurodegener. 10 2021 44 10.1186/s40035-021-00269-8 34740367
160 Epelbaum S. Burgos N. Canney M. Matthews D. Houot M. Santin M.D. Desseaux C. Bouchoux G. Stroer S. Martin C.J.A.s.R. Therapy, Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer's disease with an implantable ultrasound device Alzheimer's Res. Ther. 14 2022 1 13 34980257
161 Yemane P.T. Åslund A.K.O. Snipstad S. Bjørkøy A. Grendstad K. Berg S. Mørch Y. Torp S.H. Hansen R. Davies C.d.L. Effect of ultrasound on the vasculature and extravasation of nanoscale particles imaged in real time Ultrasound Med. Biol. 45 2019 3028 3041 10.1016/j.ultrasmedbio.2019.07.683 31474384
162 Arvanitis C.D. Vykhodtseva N. Jolesz F. Livingstone M. McDannold N. Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model J. Neurosurg. 124 2016 1450 1459 26381252
163 Wu S.K. Chiang C.F. Hsu Y.H. Lin T.H. Liou H.C. Fu W.M. Lin W.L. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer Int. J. Nanomed. 9 2014 4485 4494 10.2147/ijn.s68347
164 Barzegar-Fallah A. Gandhi K. Rizwan S.B. Slatter T.L. Reynolds J.N.J. Harnessing ultrasound for targeting drug delivery to the brain and breaching the blood–brain tumour barrier Pharmaceutics 14 2022 2231 36297666
165 Baek H. Lockwood D. Mason E.J. Obusez E. Poturalski M. Rammo R. Nagel S.J. Jones S.E. Clinical intervention using focused ultrasound (FUS) stimulation of the brain in diverse neurological disorders Front. Neurol. 13 2022 880814
166 Naor O. Krupa S. Shoham S. Ultrasonic neuromodulation JNEng 13 2016 031003
167 Rabut C. Yoo S. Hurt R.C. Jin Z. Li H. Guo H. Ling B. Shapiro M.G. Ultrasound technologies for imaging and modulating neural activity Neuron 108 2020 93 110 33058769
168 Scarcelli T. Jordão J.F. O'reilly M.A. Ellens N. Hynynen K. Aubert I.J.B.s. Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice Brain stimulation 7 2014 304 307 24629831
169 Shin J. Kong C. Lee J. Choi B.Y. Sim J. Koh C.S. Park M. Na Y.C. Suh S.W. Chang s.r. therapy, Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model Alzheimer's Res. Ther. 11 2019 1 15 30611304
170 Chen S. Nazeri A. Baek H. Ye D. Yang Y. Yuan J. Rubin J.B. Chen H. A review of bioeffects induced by focused ultrasound combined with microbubbles on the neurovascular unit J. Cereb. Blood Flow Metab. 42 2022 3 26 34551608
171 McMahon D. Mah E. Hynynen K. Angiogenic response of rat hippocampal vasculature to focused ultrasound-mediated increases in blood-brain barrier permeability Sci. Rep. 8 2018 12178 10.1038/s41598-018-30825-8
172 Nosrati R. Abnous K. Alibolandi M. Mosafer J. Dehghani S. Taghdisi S.M. Ramezani M. Targeted SPION siderophore conjugate loaded with doxorubicin as a theranostic agent for imaging and treatment of colon carcinoma Sci. Rep. 11 2021 13065 10.1038/s41598-021-92391-w
173 Koerselman M. Morshuis L.C. Karperien M. The use of peptides, aptamers, and variable domains of heavy chain only antibodies in tissue engineering and regenerative medicine Acta Biomater 170 2023 1 14 37517622
174 Ni S. Zhuo Z. Pan Y. Yu Y. Li F. Liu J. Wang L. Wu X. Li D. Wan Y. Recent progress in aptamer discoveries and modifications for therapeutic applications ACS Appl. Mater. Interfaces 13 2020 9500 9519 32603135
175 Kamali H. Nosrati R. Malaekeh-Nikouei B. Chapter 1 - nanostructures and their associated challenges for drug delivery Kesharwani P. Jain N.K. Hybrid Nanomaterials for Drug Delivery 2022 Woodhead Publishing 1 26
176 Hu Z. Zhang H. Zhang Y. Wu R.a. Zou H. Nanoparticle size matters in the formation of plasma protein coronas on Fe3O4 nanoparticles Colloids Surf. B Biointerfaces 121 2014 354 361 10.1016/j.colsurfb.2014.06.016 24974013
177 Sakulkhu U. Mahmoudi M. Maurizi L. Coullerez G. Hofmann-Amtenbrink M. Vries M. Motazacker M. Rezaee F. Hofmann H. Significance of surface charge and shell material of superparamagnetic iron oxide nanoparticle (SPION) based core/shell nanoparticles on the composition of the protein corona Biomater. Sci. 3 2015 265 278 10.1039/C4BM00264D 26218117
178 De Macedo E.F. Santos N.S. Nascimento L.S. Mathey R. Brenet S. de Moura M.S. Hou Y. Tada D.B. Interaction between nanoparticles, membranes and proteins: a surface plasmon resonance study Int. J. Mol. Sci. 24 2022 591 36614033
179 Kopac T. Protein corona, understanding the nanoparticle–protein interactions and future perspectives: a critical review Int. J. Biol. Macromol. 169 2021 290 301 33340622
