==== Front Int J Mol Sci Int J Mol Sci ijms International Journal of Molecular Sciences 1422-0067 MDPI 33266216 10.3390/ijms21239123 ijms-21-09123 Review Aptamer-Functionalized Nanoparticles in Targeted Delivery and Cancer Therapy Fu Zhaoying 1* Xiang Jim 2* 1 Institute of Molecular Biology and Immunology, College of Medicine, Yanan University, Yanan 716000, China 2 Division of Oncology, University of Saskatchewan, Saskatoon, SK S7N 4H4, Canada * Correspondence: yadxfzy@yau.edu.cn (Z.F.); jim.xiang@usask.ca (J.X.) 30 11 2020 12 2020 21 23 912320 10 2020 11 11 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Using nanoparticles to carry and delivery anticancer drugs holds much promise in cancer therapy, but nanoparticles per se are lacking specificity. Active targeting, that is, using specific ligands to functionalize nanoparticles, is attracting much attention in recent years. Aptamers, with their several favorable features like high specificity and affinity, small size, very low immunogenicity, relatively low cost for production, and easiness to store, are one of the best candidates for the specific ligands of nanoparticle functionalization. This review discusses the benefits and challenges of using aptamers to functionalize nanoparticles for active targeting and especially presents nearly all of the published works that address the topic of using aptamers to functionalize nanoparticles for targeted drug delivery and cancer therapy. aptamernanoparticledeliverycancer ==== Body 1. Introduction The ideal cancer therapeutics should be capable of exerting maximum destruction on cancer cells while being able to keep damage to healthy tissues at a minimum. Many anticancer drugs are toxic to cancer cells and healthy cells largely non-differentially, and the major reason that they cause more damage to cancer is because the cancer cells grow/divide more quickly. Besides, most anticancer drugs are in general evenly distributed throughout the body when administered systemically and the result is that only a very small fraction of the drugs reach the diseased site. Therefore, it is not surprising that selective delivery of anticancer drugs to cancer cells has long been a vigorous pursuit of cancer scientists. Nanoparticles have the potential to encapsulate and transport anticancer drugs to tumor tissue more effectively [1]. However, nanoparticles per se do not have specificity to cancer cells; the fact that nanoparticles accumulate preferentially in cancer sites is basically due to the enhanced permeability and retention (EPR) effect of the tumor tissue [2]. On the other hand, if nanoparticles could be functionalized by ligands capable of recognizing cancer cells specifically, they will be able to target and deliver cargoes selectively to cancer cells and thus greatly increase the therapeutic index (increasing therapeutic efficacy while reducing toxicity). To date, a number of moieties have been studied to functionalize nanoparticles for specific targeting and aptamer is one of them [3]. This paper discusses aptamer-functionalized nanoparticles in targeted delivery for cancer therapy. It first compares passive and active targeting of nanoparticles, then describes the advantages of using aptamers to functionalize nanoparticles for active targeting, explains the strategies to conjugate aptamers to nanoparticles, and summarizes nearly all of the existing aptamer-functionalized nanoparticles used thus far to study targeted delivery to cancer cells. It finally briefly discusses the challenges facing active targeting. 2. Passive vs. Active Targeting of Nanoparticles Passive targeting of nanoparticles refers to the passive accumulation of nanoparticles in the tumor tissue, which is generally attributed to the enhanced permeability and retention effect. The concept of EPR was first introduced more than 30 years ago when Maeda and colleagues found that certain macromolecules accumulate preferentially in the tumor tissue [4]. EPR is mainly the result of leakiness of the discontinuous endothelium of angiogenic tumor vasculature combined with defective lymphatic drainage of the tumor matrix, which facilitates the extravasation and accumulation of nanoparticles in tumor. It has been shown that the number of nanoparticles accumulated in tumor tissue may be 10–200 times higher than in normal tissue as a result of EPR. The EPR effect is considered to be the primary element to improve the efficacy and safety of nanotherapeutics. In fact, most of the nanomedicines marketed thus far base their increased therapeutic index mainly on the EPR effect [5]. Nevertheless, the EPR effect alone is insufficient for adequate nanoparticle accumulation, particularly in some circumstances. The EPR effect is not effective for some cancers because of tumor heterogeneity and cancer stage, is even not applicable to some types of cancers, and it is not effective in some patients because of individual differences. A survey of the literature in this area from 2005 to 2015 that included 232 data sets showed that only a median of 0.7% of the systemically administered nanoparticle dose could reach the solid tumor in mouse models [6]; multivariate analysis of the pertinent parameters indicated that tumor type, tumor model, and nanomaterial properties are the major factors to affect the delivery efficiency of the nanoparticles. Research also found that the high interstitial fluid pressure of tumor tissue impedes the extravasation of nanoparticles [7]; some particles that have entered the tumor intercellular space via EPR effect may be forced back into the blood circulation because of the high fluid pressure within the tumor interstitium. It is manifest that blood cancers, very early stage tumors, and small metastasized cancers do not have or have only insignificant EPR effect. In addition, because of tumor heterogeneity, the EPR effect is very poor or not shown in some types of cancers and even in different regions of the same tumor [8]. Clinical observations have also indicated that the EPR effect exhibits significant individual variations among patients; the nanomedicines do not increase the therapeutic efficacy in some subpopulations of the patients [9]. Finally, and most importantly, it is now reckoned that the EPR effect chiefly works in animal models rather than in humans [10]; in patients, their effects are just uncertain (because of interpatient variability); these uncertainties pose the most serious challenge to the rationale of nanomedicine development based on the EPR effect and to the clinical translation of the nanotherapeutics. All the above problems warrant the development of a more effective way to deliver nanoparticles to the site of interest. Active targeting, which is achieved by conjugating tumor specific ligands to the surface of nanoparticles, can provide a means to complement the EPR effect or solve the aforementioned problems. Common classes of targeting ligands that can functionalize nanoparticles include antibodies or antibody fragments, aptamers, carbohydrates, human transferrin protein, peptides, and vitamins such as folate, etc. Representative tumor biomarkers that can be recognized by the targeting ligands include epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor 2 (HER2), Mucin-1 (MUC1), nucleolin, platelet-derived growth factor receptor β (PGFRβ), prostate specific membrane antigen (PSMA), transferrin receptor, folate receptor, and so on. The foremost advantage of actively targeted nanoparticles over passively targeted nanoparticles is that they can add on to or improve the EPR effect. An actively targeted nanoparticle can first enter the tumor tissue via the EPR effect and then target cancer cells through specific ligand recognition of the tumor biomarker. In addition, active targeting can augment the EPR effect by having more particles entering than leaving the tumor interstitium because the particles that already enter stick to the cancer cells and thus lower the concentration of the free nanoparticles in the interstitial space. Studies have already demonstrated that actively targeted nanoparticles tend to accumulate more efficiently in the tumor tissue through their selective binding to receptors on the cancer cells when they enter the tumor interstitium [11]. The ligand-mediated active targeting not only helps nanoparticles selectively reach the tumor; it may also promote cellular internalization of the nanoparticles through receptor-mediated endocytosis since some receptors have the intrinsic property to internalize when bound by a ligand. The importance of cellular internalization should be obvious when we think of the fact that most anticancer drugs exert their actions inside cancer cells. Although nanoparticles themselves can get into the cell through clathirin-mediated endocytosis or fluid-phase pinocytosis, conjugation of active ligands to them may boost the process. Receptor-mediated engulfment has already been observed in many specific ligand conjugated nanoparticles; typical examples of aptamer-mediated cellular internalization include the PSMA-targeting A10 aptamer mediated as well as the nucleolin-targeting AS1411 aptamer mediated internalizations [12,13]. Although the targeting ligands can be conjugated with the anticancer agents such as siRNAs and chemotherapeutics directly, the advantage of using nanoparticles is that they can deliver large amounts of drug payload or diversified therapeutics to cancer cells per delivery and biorecognition event [14]. Having a nanoparticle encapsulate diverse therapeutic ingredients could potentially offer synergistic tumor killing effects (e.g., combining any of these anticancer strategies like chemotherapy, gene silencing, immunotherapy, photodynamic therapy, photothermal therapy, and thermodynamic therapy, etc.). Encapsulating different therapeutics within a nanoparticle may also help to overcome or reduce multiple drug resistance (MDR) because MDR usually does not occur to different drugs at the same time or at the same degree, and the mechanisms of MDR differs with different drugs. One example is that nanoparticle-mediated combination of chemotherapy and photodynamic therapy can overcome drug resistance through invoking multiple anticancer mechanisms including cytotoxicity and significantly enhanced production of reactive oxygen species [15]. Active targeting of nanoparticles could also have additive therapeutic effects by exploiting the drug-carrying and receptor-inhibiting actions at the same time. For instance, anticancer reagent-containing nanoparticles functionalized with HER2-targeting ligand, in addition to delivering the therapeutic ingredients into the target cells can, meanwhile, inhibit the activity of the targeted receptors or remove the receptors from the cell surface by means of internalization [16]. 3. Aptamer-Functionalized Nanoparticles in Actively Targeted Drug Delivery Aptamers are short single-stranded DNA or RNA molecules with defined three-dimensional structures that can selectively bind to target molecules with high affinity [17]. Aptamers are usually produced by selecting them from a large random sequence pool with the technology systematic evolution of ligands by exponential enrichment (SELEX). In addition to their superb binding specificity and affinity, aptamers have a number of other favorable features that together make them very suitable molecules to functionalize nanoparticles for actively targeted delivery. Aptamer functionalized nanoparticles have already demonstrated their effectiveness in targeted delivery of anticancer drugs in numerous preclinical and animal studies, though none of them have as yet entered clinical trial or application. 3.1. The Advantages of Using Aptamers to Functionalize Nanoparticles Aptamers have a very broad spectrum of target recognition and binding; they have little or no immunogenicity; they can easily be end-attached with a chemical group to conjugate nanoparticles; they are small (only a few nanometers in diameter) and will not increase nanoparticle size significantly after coupling; they are relatively easy to make and to store [17]. Those are the general properties of aptamers that make them one of the best choices to functionalize nanoparticles. Up to now, quite a few aptamers have been used to functionalize nanoparticles for targeted delivery to cancer cells (Table 1). Apart from the abovementioned characteristics, aptamers have a unique advantage that is related to their production—the establishment of the cell-SELEX technique and its improvements have made the aptamer an especially useful ligand to be used to construct the cancer-targeting nanocarriers (Figure 1). After the setting up of the prototype SELEX technology in 1990, a selection strategy known as cell-SELEX was developed in 2003 that uses whole (living) cells to select aptamers targeting cell surface molecules [215]. This technique allows for the isolation of cell-recognizing aptamers without prior knowledge of the target molecule(s). In 2006, a negative selection (or counter-selection) process was integrated into the original cell-SELEX strategy, which makes it possible to obtain cell-specific aptamers on researcher’s will [216]. In the new cell-SELEX procedure, the negative selection is performed first, wherein the negative-selection cells (these may be normal cells or any untargeted cells and several different types of cells may be used) are used to absorb the undesired or non-specific aptamers (In this step, the undesired or non-specific oligonucleotides in the pool are removed as they bind to the negative-selection cells). The negative selection is followed by positive selection that is conducted basically in the same way as the conventional cell-SELEX strategy and aims to discard the oligonucleotides that do not bind to the positive-selection cells (usually, certain types of cancer cells or any researcher-intended cells are used for this purpose). Thus, by employing the new cell-SELEX technique, one is able to generate aptamers that can specifically recognize cell surface receptors (or molecules) and thus can effectively differentiate cancer cells from normal cells. More importantly, with certain added steps, the cell-SELEX technique can still select aptamers that not only specifically recognize or target cell surface receptors but also get into the cells through receptor mediated internalization [217]. 3.2. Strategies of Conjugating Aptamers to Nanoparticles Aptamers can be conjugated to nanoparticles directly or indirectly via a linker molecule (a bridge or spacer). Both direct and indirect conjugation can be achieved either covalently or non-covalently (Figure 2). In covalent conjugation, a functional group (such as a primary amino group or a thiol group) is usually attached to one terminus of the aptamer, which can react with the functional group (such as the carboxylic acid group, the maleimide group, and the aldehyde group) on the surface of the nanoparticle or at one end of the linker molecule, or react with the gold or other metal element or inorganic molecule for inorganic nanoparticles. Common examples of covalent conjugation include the carboxylic acid group and the amino group interaction that results in an amide (or carboxamide) linkage, the carboxylic acid group and the thiol group interaction that results in a thioester bond, the carboxylic acid group and the alcohol group interaction that results in an ester bond, the primary amine group and thiol group interaction that results in a thioamide bond, the thiol group and the thiol group interaction that results in a disulfide bond, and the thiol group and the gold or silver interaction that results in a Au–S or Ag-S bond. Non-covalent conjugation strategies include high affinity interactions and electrostatic interactions. The former includes avidin–biotin and streptavidin–biotin interactions. The latter are commonly seen when a linker molecule is used, in which case the opposite charges on the linker molecule and on the extended oligonucleotide sequence of the aptamer interact, but also include the using of histidine tags. Most of the aptamer–nanoparticle conjugates reported thus far utilized the direct and covalent strategy. According to Farokhzad and colleagues [11], “covalently linked bioconjugates may result in enhanced stability in physiological salt and pH whilst avoiding the unnecessary addition of biological components (i.e., streptavidin); thus minimizing immunological reactions and potential toxicity”. Fewer studies used bridge or spacer molecule to link aptamer and nanoparticle together. These are in consideration of avoiding any possible steric or spatial restrictions on aptamer’s binding to target molecule, but an associated problem is the increased size of the conjugates. Several aptamer-nanoparticle constructions, including both direct and indirect linkage, used the avidin–biotin or the streptavidin–biotin system. These interactions are very stable but the bulk of the formulation may increase considerably and potential immunological rejection problems might also result. 3.3. Aptamer-Functionalized Nanoparticles in Pre-Clinical Studies Up till now, quite a lot of aptamer-conjugated nanoparticles have been developed that can target specific cancer cells, deliver various therapeutic agents into cancer cells, and result in cancer cell toxicity in vitro (e.g., inhibit cell proliferation and induce apoptosis of cultivated cancer cells) and/or anticancer effects in vivo (e.g., inhibit xenograft tumor formation in nude mouse model). An inclusive list of nearly all aptamer-conjugated drug-delivering nanoparticles that have been studied thus far with their characteristics and sources is provided in Table 1. A schematic representation of the action process of aptamer-functionalized nanoparticles acting on a cancer cell is shown in Figure 3. Farokhzad and Langer et al. [18] first performed the proof of concept study of using the aptamer to functionalize nanoparticles for actively targeted drug delivery in 2004. The authors synthesized the nanoparticles of poly (lactic acid)-block-polyethylene glycol copolymer with a terminal carboxylic acid functional group (PLA-b-PEG-COOH) and encapsulated the nanoparticles with rhodamine-labeled dextran as a model drug; they then covalently attached the PSMA-targeting A10 RNA aptamer to the nanoparticles through the reaction of the amino groups on the 3′ end of the aptamers with the carboxylic acid groups on the surface of the nanoparticles. These aptamer–nanoparticle conjugates were demonstrated to be able to target the PSMA-positive prostate LNCaP cells significantly more efficiently compared with the same PEGylated nanoparticles without aptamer conjugation and could get internalized into the cells. The uptake of these conjugates was not boosted in the PC3 cells that are also prostate-derived but do not express PSMA. A similar nanoparticle-aptamer construction, which used the same PSMA-targeting aptamer but used poly (lactic-co-glycolic acid)-block-polyethylene glycol copolymer with a terminal carboxylic acid group (PLGA-b-PEG-COOH) as nanomaterial and encapsulated the anticancer drug Docetaxel within the nanoparticles, was later assessed both in vitro and in vivo by the same laboratory. The in vivo results showed that the aptamer-targeted drug-loaded nanoparticles exhibited significantly more reduced toxicity (side effects) in the nude mice as measured by mean body weight loss than non-targeted nanoparticles, and intratumoral injection of these aptamer-targeted drug-loaded nanoparticles resulted in complete tumor reduction in five of seven LNCaP xenograft nude mice compared with two of five for non-targeted nanoparticles [19]. Up to the present time, polymers, which include miscellaneous classes with PLGA-PEG being the most frequently used, remain the most used nanomaterials to construct aptamer functionalized nanoparticles to study targeted delivery for cancer therapy, followed by lipid based materials, particularly liposomes and nucleic acid based nanoparticles, including either DNA or RNA. Other organic nanomaterials that have been used include dendrimers, chitosan, proteins/peptides, or hybrids of the above. There are also many inorganic nanomaterials that have been studied in this area, including gold (Au) compounds, silver (Ag), mesoporous silica, graphene based, Calcium carbonate, ZnO, iron, etc. Other and special inorganic nanomaterials include magnetic nanomaterials, quantum dot based nanoparticles, and so on. In addition, organic and inorganic hybrids have also been used. Refer to Table 2 for a classified list of these nanoparticles and nanomaterials with their payloads, targets, related cancers, etc. 4. Challenges Facing Actively Targeted Delivery Although active targeting holds much promise, several challenges exist. These include the increased complexity of synthesis and purification, the increased cost to make the conjugants, the alterations of nanoparticle properties, choosing a suitable tumor marker or receptor to target, and so forth. 4.1. Potential Alterations of Nanoparticle and Ligand Properties after Conjugation Ligand conjugation may alter the properties of the nanoparticle. Not only will it increase nanoparticle size; it can also change the charge and modify the conformation of the nanoparticle. The change of nanoparticle size is likely to affect their pharmacokinetics; the change of nanoparticle charge will probably complicate their cellular uptake; the change of nanoparticle conformation may influence the binding feature of the attached ligand because of inadequate steric freedom or decreased orientation. All these must be taken into consideration in making actively targeting nanoparticles. Although conjugating ligands to nanoparticles might change the pharmacokinetic property of the nanoparticles, this may not be a problem for aptamer conjugation because aptamers are very small, about 2–3 nm in length, in comparison with the drug-carrying nanoparticles, which is typically around 100 nm or larger in diameter. In fact, no literature has reported any alterations in the pharmacokinetics of nanoparticles following aptamer coupling. Aptamers are commonly modified before therapeutic use. The purpose of modification is to increase their stability against nuclease degradation or prolong their half-life against kidney filtration. Aptamer modification can be performed during selection or after selection. The former aims at stabilizing the aptamers against nucleases. The latter aims at prolonging renal retention and is frequently done with PEGylation, covalent attachment of PEG to one end of the aptamer. Therefore, the attachment of aptamers to a nanoparticle will favorably increase their stability. However, conjugation of aptamers to a nanoparticle might interfere with their proper folding and change their binding specificity and affinity. For example, the surface charge of the nanoparticle and the density of the attached aptamers on the nanoparticle may both affect their folding and three-dimensional structure. In addition, aptamers that are coupled directly to a nanoparticle may not recognize and bind their target effectively because there is no sufficient space (stereo-interference effect). Sometimes, the orientation of aptamer immobilization may also affect aptamer binding. All these problems should be considered by the researchers and optimum parameters or corresponding resolving measures be taken. For instance, the density and the orientation of attached aptamers can be investigated and optimized, and when stereo-interference occurs, the researchers can consider the use of a spacer molecule. 4.2. Selection of Suitable Tumor Marker or Receptor The ideal receptor for targeted therapy is one that is exclusively presented on the tumor cells but not on the healthy cells. However, such a receptor may not exist in reality. What we can do is to choose the receptors that have a higher expression level on tumor cells than on healthy cells. The expression of the target receptors on healthy cells, though at a lower level, still carries a potential risk of off target binding. What is more, binding to these receptors may consume or waste the therapeutic nanoparticles and lower its concentration to reach the tumor. 4.3. The “Binding Site Barrier” Effect Aside from the challenges mentioned above, there may also be the “binding site barrier” problem, which refers to a situation wherein high affinity binding to target cells prevents in-depth and uniform penetration of the targeted therapeutics into the tumor tissue. This phenomenon was first observed by Weinstein and colleagues [218,219] with antibodies, which showed that (1) antibody–antigen binding in tumor-retarded antibody percolation and (2) high antibody affinity had a tendency to decrease antibody percolation. The explanation to the phenomenon that higher-affinity antibodies penetrate the tumor tissue less efficiently than lower-affinity antibodies is that during tissue penetration, the higher-affinity antibodies bind tightly to the cells they first meet and so there are fewer free antibody molecules available; in contrast, lower-affinity antibodies tend to bypass these target cells and can penetrate deeper. Although the “binding site barrier” was originally demonstrated in antigen–antibody interaction, it may be reasonably extrapolated to the actively targeted nanoparticles and a similar phenomenon has in fact be observed by Miao et al. [220] using anisamide ligand targeted lipid-coated calcium phosphate nanoparticles. Therefore, it is essential to seek a balance between the affinity of active tumor targeting and the depth of nanoparticle penetration; trial and error may be necessary [221]. 5. Conclusions The first nanotechnology-based anticancer medicine was approved by the United States Food and Drug Administration (FDA) in 1996, which used PEGylated liposomes to encapsulate the chemotherapeutic drug doxorubicin. Today, about ten nanoparticle based medications are on the market (approved by FDA or other agencies) for cancer therapy [14,222]. All of them are non-targeted or passively targeted. These nanodrugs could delay the clearance or prolong the half-life of the drugs and reduce side-effects to a certain degree. However, only a modest increase in therapeutic efficacy could be observed and the undesired off-target problem still exists, which calls for the development of active targeting of nanoparticles. At the present time, more than a dozen nanoparticles for cancer therapy are undergoing clinical trials [2], of which several are actively targeted, but none of them are aptamer-functionalized. Actively targeted, especially aptamer-functionalized, nanoparticles hold great promise for future nanodrug development and applications. Therefore, more efforts are needed to further the investigation in this area, to refine the experiments and overcome the obstacles for clinical translation. Some obstacles for developing aptamer conjugated-nanoparticles into clinical use include insufficient data about their off-target effects and toxicity either in animals or in human. Venditto and Szoka once notified in their review paper titled Cancer nanomedicines: so many papers and so few drugs published in 2013 that “if we are truly interested in bringing more drugs into the clinic we should focus less on our publication record and more on devising scientific progress that translates into patient treatment” [223]. The same situation exists in the investigation of aptamer-functionalized nanoparticles when we take notice of the fact that more than two hundred papers have been published so far but none of the aptamer-functionalized nanoparticles have entered clinical trials, not to mention clinical application. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Funding This work was supported by NSFC, grant number 81760732. Conflicts of Interest The author declares no competing interests. Abbreviations 3WJ-RNA a highly stable three-way junction (3WJ) motif from phi29 packaging RNA 5-FU 5-fluorouracil ALCL anaplastic large cell lymphoma ALK anaplastic lymphoma kinase ALL acute lymphoblastic leukemia, also known as T-cell acute lymphoblastic leukemia AML-M2 acute myeloid leukemia subtype 2 APTES (3-aminopropyl) triethoxysilane BSA bovine serum albumin cMet hepatocyte growth factor receptor COOH (terminal) carboxylic acid group CSC cancer stem cell CTC circulating tumor cell CUR-NP curcumin-loaded lipid-polymer-lecithin hybrid nanoparticle Cyt c cytochrome c DAU daunorubicin DGL dendrigraftpoly-L-lysines DOTAP 1,2-dioleoyl-3-trimethylammonium-propane DNR daunorubicin DOX doxorubicin dsDNA double-stranded DNA DSPE 1,2-distearoyl-sn-glycero-3-phosphoethanolamine EGFR Epidermal growth factor receptor EHH electrostatic adsorption, hydrogen bonding, and hydrophobic interaction Ehrlich’s ACC Ehrlich’s ascites carcinoma cell ELP elastin-like polypeptide EpCAM epithelial cell adhesion molecule EPI epirubicin FGFR1 fibroblast growth factor receptor type-1 FMSN fluorescent mesoporous silica nanoparticle FN fibronectin FO Ferric oxide FoxM1 Forkhead box M1 Gd:SrHap gadolinium-doped luminescent and mesoporous strontium hydroxyapatite GMNP gold-coated magnetic nanoparticle GNP gold nanoparticle GO Graphene oxide GPN gefitinib-loaded poly (lactic co-glycolic acid) nanoparticle GQD graphene quantum dot GST glutathione S-transferase HA Hyaluronic acid HAS-CS human serum albumin coated with chitosan HBLL human B cell leukemia and lymphoma HCC Hepatocellular carcinoma HER3 human epidermal growth factor receptor 3 His hexahistidine HMME is a photosensitizer HPA heparanase HPAEG poly(2-((2-(acryloyloxy)ethyl)disulfanyl)ethyl 4-cyano-4-(((propylthio)carbonothioyl)-thio)-pentanoate-co-poly(ethylene glycol) methacrylate) HSP71 heat shock cognate 71 kDa protein HTT hyperthermia therapy IL-6R interleukin-6 receptor IONP Iron oxide nanoparticle KG6E glutamic acid-modified dendritic poly(L-lysine) system KLA (KLAKLAK)2 peptide LP-DNA liposome-polycation-DNA MAA methacrylamide MAGE melanoma-associated peptide antigen MAL maleimide MASI N-(methacryloxy)succinimide MCS Myristylated Chitosan MMA methyl methacrylate MOF (mesoporous) metal-organic framework MPC mesoporous carbon MPEG Poly(ethylene glycol) methyl ether M-PLGA mannitol-functionalized poly(lactide-co-glycolide) MSN Mesoporous silica nanoparticle mTEC mouse tumor endothelial cell MDR multiple drug resistance MUC1 Mucin-1 NHS N-hydroxysuccinimide NIR PLN near infrared-persistent luminescence nanomaterials NMOF amino-triphenyl dicarboxylate-bridged Zr4+ metal-organic framework nanoparticle NP nanoparticle NSCLC non-small cell lung cancer ONT oligonucleotide PAA polyacrylic acid PAM Peptide amphiphile micelle PAMAM polyamidoamine PBABT poly (butylene adipate-co-butylene terephthalate) PCL poly(ε-capro-lactone) PDA hydrochloride dopamine PDGFR platelet-derived growth factor receptor PEC polyelectrolyte complexe PEEUA polyethylenimine-urocanic acid PEG polyethylene glycol PEI polyethylene imine PF127 Pluronic F127 PFK15 1-(4-pyridyl)-3-(2-quinoline)-2-propyl-1-one (an aerobic glycolysis inhibitor) PFOB Perfluorooctylbromide PGFRβ platelet-derived growth factor receptor β P-gp P-glycoprotein PLA poly(lactic acid) PLGA poly(lactic-co-glycolic acid) PLK1 Polo-Like Kinase 1 PLL poly (L-lysine) pPEGMA-PCL-pPEGMA poly(poly(ethylene glycol) methacrylate)-poly(caprolactone)-poly(poly(ethylene glycol) methacrylate) PTK7 protein tyrosine kinase-7 PTT Photothermal therapy PVP poly (N-vinylpyrrolidone) PβAE poly (β amino ester) QD quantum dot RBCm red blood cell membrane SATB1 special AT-rich sequence binding protein 1 SPION superparamagnetic iron oxide nanoparticles SPMFN Superparamagnetic Ferroarabinogalactan Nanoparticles TAG-72 tumor-associated glycoprotein 72 TD thiolated dextran TiO2 titanium dioxide TLR Toll-like receptor TLR4-siRNA TM-JM1/2 transmembrane-juxtamembrane 1/2 domain TMPyP 5, 10, 15, 20-tetra (phenyl-4-N-methyl-4-pyridyl) porphyrin TMPyP4 5,10,15,20-tetrakis(1-methylpyridinium-4-yl) porphyrin TNBC triple-negative breast cancer TPGS D-α-tocopheryl polyethylene glycol 1000 succinate TSP thermosensitive polymer UCNP up-conversion luminescent NaYF4 Yb(3+)/Er(3+) nanoparticle VEGF vascular endothelial growth factor β-CD β-cyclodextrin Figure 1 Selection procedure of cell-internalizing DNA aptamer using cell-SELEX. Figure 2 Common strategies of nanoparticle-aptamer conjugation. Figure 3 Schematic representation of aptamer-functionalized nanoparticle acting on a cancer cell. ijms-21-09123-t001_Table 1Table 1 Aptamer-functionalized nanoparticles designed for actively targeted drug delivery and cancer therapy in laboratory investigation stage. Aptamer Nanomaterial Payload Conjugation Size (nm) Target Cancer/Cell Line Level Ref. A10, RNA PLA-PEG-COOH Rho-labeled dextran Direct #, covalent ≈264 PSMA Prostate cancer in vitro [18] A10, RNA PLGA-PEG-COOH Docetaxel Direct, covalent ≈168 PSMA Prostate cancer in vitro + in vivo [19] A10, RNA PLGA-PEG-COOH Cisplatin Direct, covalent ≈155 PSMA Prostate cancer in vitro [20] sgc8c, DNA Au-Ag nanorod Photothermal therapy Direct, thiol linkage No data CCRF-CEM cell ALL in vitro [21] A10, RNA SPION Doxorubicin Direct, covalent 66.4 ± 1.5 PSMA LNCaP cell line in vitro [22] sgc8c, DNA PAMAM dendrimer None Direct, covalent ≈8 CCRF-CEM cell ALL in vitro [23] AS1411, DNA Liposome Cisplatin Covalent, to cholesterol ≈200 Nucleolin MCF-7 cells in vitro [24] S2.2, DNA PLGA-COOH Paclitaxel Covalent, DNA spacer ≈225.3 Mucin-1 Breast cancer in vitro [25] AS1411, DNA PEG-PLGA Paclitaxel Direct, covalent 156 ± 54.8 Nucleolin Glioma in vitro + in vivo [26] No name, DNA DNA icosahedra Doxorubicin Direct, covalent 28.6 ± 5.0 Mucin-1 MCF-7 cells in vitro [27] A9, RNA SPION Doxorubicin ONT linker, base pairing 65 ± 12 PSMA LNCaP cell line in vitro + in vivo [28] A9, RNA ONT-PAMAM dendrimer Doxorubicin ONT linker, base pairing No data PSMA Prostate cancer in vitro + in vivo [29] No name, RNA QD-PMAT-PEI siRNA Chimera with siRNA 66.3–76.5 PSMA C4–2B cells in vitro [30] XEO2mini, RNA Hybrid lipid-polymer Docetaxel Direct, covalent 50–100 PC3 cells Prostate cancer in vitro [31] AS1411, DNA PLGA-lecithin-PEG Paclitaxel Covalent, to PEG 60–110  Nucleolin GI-1 and MCF-7 cells in vitro [32] AS1411, DNA PLGA Paclitaxel Direct, amide linking ≈200 Nucleolin GI-1 cells in vitro [33] AS1411, DNA PEG-PCL Docetaxel, DiR, coumarin-6 Direct, covalent 170.6 Nucleolin bEnd.3 and C6 cells in vitro + in vivo [34] AS1411, DNA Mesoporous silica Gold nanorods * ONT linker, base pairing ≈60 Nucleolin MCF-7 cells in vitro [35] GMT8, DNA PEG-PCL Docetaxel Direct, covalent 111.9 ± 64.2 U87 cells glioblastoma in vitro + in vivo [36] AS1411, DNA Gd:SrHap nanorod Doxorubicin Direct, covalent 153 Nucleolin MCF-7 cells in vitro [37] AS1411, DNA Mesoporous silica Doxorubicin Electrostatic binding ≈140 Nucleolin MCF-7 cells in vitro [38] AS1411, DNA Mesoporous silica Fluorescein Sulfo-GMBS linker 190 Nucleolin MDA-MB-231 in vitro [39] Sgc8, DNA Mesoporous silica Doxorubicin Avidin-biotin interaction ≈150 PTK7 CEM cells in vitro [40] AS1411, DNA Liposome Doxorubicin Covalent, to cholesterol ≈200 Nucleolin MCF-7 breast cancer cells in vitro + in vivo [41] A10, RNA H40-PLA-PEG Doxorubicin Covalent, to PEG ≈69 PSMA CWR22Rν1 cells in vitro + in vivo [42] 5TR1, DNA SPION Epirubicin Direct, covalent ≈57 Mucin-1 carcinoma C26 cells in vitro [43] No name, RNA Hollow gold nanosphere Doxorubicin Direct, thiol–Au bonds ≈42 CD30 Lymphoma in vitro [44] sgc8c, DNA Aptamer DNA Antisense ONT to P-gp Direct, covalent 218 CCRF-CEM cell ALL in vitro [45] Sgc8, DNA DNA nanotrains Gold, DOX, DNR, and EPI Direct, covalent No data PTK7 ALL in vitro + in vivo [46] No name, DNA Dextran-ferric oxide None (HTT) PDPH linker ≈70 HER2 SK-BR3 cells in vitro [47] AS1411, DNA PLGA-PEG Vinorelbine Direct, covalent <200 Nucleolin MDA-MB-231 cells in vitro [48] No name, DNA Liposome TSP Avidin-biotin interaction No data PDGFR Breast cancer cells in vitro [49] AS1411, DNA PEGylated liposome Anti-BRAF siRNA Via PEG linker ≈150 Nucleolin A375 tumor xenograft in vivo [50] No name, RNA PLGA-lecithin-PEG Curcumin Direct, covalent 90 ± 1.9 EpCAM HT29 cells in vitro [51] AS1411, DNA pPEGMA-PCL-pPEGMA Doxorubicin Direct, covalent ≈140 Nucleolin MCF-7 and PANC-1 cells in vitro [52] AS1411, DNA Gold nanoparticle Doxorubicin or AZD8055 Dithiolane linker No data Nucleolin MCF-7, el202 and OMM1.3 in vitro [53] A10, RNA and DUP-1 PEG-gold nanostar None (PTT) Direct, di- sulfide bonds 61.90 ±1.61 Prostate cell Prostate cancer in vitro [54] No name, DNA Chitosan SN38 Direct, covalent ≈200 Mucin-1 Colon cancer HT-29 cells in vitro [55] AS1411, DNA Gold nanoparticle Doxorubicin and TMPyP4 Tethered by 21 bp DNA 38.7 ± 1.4 Nucleolin HeLa and MCF-7R cells in vitro [15] No name, RNA Liposome Doxorubicin Tethered by linker DNA 90–100 PSMA LNCaP cells in vitro + in vivo [56] No name, DNA Gold nanoparticle Protein With a His-tag 83.0 ± 1.3 His or GST HeLa and A431 cells in vitro + in vivo [57] A10–3.2, RNA PEG-PAMAM MicroRNA Direct, covalent 177 ± 17.5 PSMA Prostate cancer in vitro + in vivo [58] A10–3.2, RNA Atelocollagen MicroRNA Direct, covalent 221 ± 6.9 PSMA Prostate cancer in vivo [59] AS1411, DNA PF127-β-CD-PEG-PLA Doxorubicin Covalent, to PF127 ≈39.15 Nucleolin MCF-7 cells in vitro + in vivo [60] No name, RNA PLGA Nutlin-3a Direct, covalent 292 ± 10 EpCAM ZR751, MCF-7, SKOV3 in vivo [61] No name, RNA PLGA-PEG Doxorubicin Direct, amide linking 136 ± 0.21 EpCAM Non-small cell lung cancer in vitro + in vivo [62] No name, RNA PEI EpCAM siRNA Electrostatic interaction 198 ± 14.2 EpCAM MCF-7 and WERI-Rb1 cells in vivo [63] HB5, DNA Mesoporous silica-carbon Doxorubicin thiol-amine link to PEG ≈140 HER2 SK-BR-3 cells in vivo [64] No name, DNA Au–GO None (PTT) Direct, Au–S bond No data Mucin-1 MCF-7 cells in vivo [65] sgc8c, DNA Gold nanorod Hyperthermia therapy Direct, Au–S bond No data CCRF-CEM cell ALL in vitro [66] * No name, RNA PEG-PLGA Doxorubicin Direct, covalent 136 ± 0.21 EpCAM MCF-7 cells in vitro [67] AS1411, DNA MOF shell, UCNP core Doxorubicin Direct, covalent ≈140 Nucleolin MCF-7 and 293 cells in vitro [68] No name, RNA GPN Gefitinib Direct, covalent No data Ets1 H1975 cells in vitro + in vivo [69] No name, DNA Hyaluronan/Chitosan 5-fluorouracil Direct, covalent 181 Mucin-1 Colorectal cancer in vitro [70] Cy5.5-AS1411 GO and MSN Doxorubicin Non-covalent No data Nucleolin MCF-7 cells in vitro [71] A15, RNA PLGA-PEG-COOH Salinomycin Direct, covalent 159.8 CD133 Osteosarcoma CSCs in vitro + in vivo [72] S2.2, DNA Graphene oxide-gold Doxorubicin Thiol–Au bonds No data Mucin-1 A549 and MCF-7 cells in vitro [73] A15, CL4; RNA PLGA Salinomycin Direct, covalent 139.7, 141.9 CD133, EGFR Hepatocellular carcinoma in vitro + in vivo [74] S2.2, DNA ZnO nanoparticle Doxorubicin APTES linkage 5–10 Mucin-1 MCF-7 cells in vitro [75] SRZ1, DNA DOTAP:DOPE liposome Doxorubicin No data ≈100 4T1 cells 4T1 cells in vitro + in vivo [76] AS1411, DNA Tocopheryl PEG-PβAE Docetaxel No data 116.3 ± 12.4 Nucleolin SKOV3 ovarian cancer cells in vitro [77] No name, DNA Chitosan and HA SN38 Direct, covalent 129 ± 3.2 Mucin-1 HT29 cells in vitro [78] S6, DNA Dendrimer MicroRNA Direct, covalent 100–200 A549 cells NSCLC cells in vitro [79] AS1411, DNA PLL-alkyl-PEI shRNA electrostatic coupling 168–183 Nucleolin A549 cells in vitro [80] AS1411, DNA GQD-FMSN Doxorubicin Direct, amide bond 72.5 Nucleolin HeLa cells in vitro [81] KW16–13, DNA PEG-gold nanorod None (PTT) Direct, covalent No data MCF10CA1h cell Human breast duct carcinoma in vitro [82] No name, DNA Au-SPION Gold for PTT Thiol–Au interaction ≈39 Mucin-1 Colon cancer in vitro [83] MA3 Iron None (HTT) Streptavidin-biotin, direct ≈296 Mucin-1 MCF-7 cells in vitro [84] No name, RNA Albumin Cisplatin Direct, amide bond ≈40 EGFR Hela cell line in vitro + in vivo [85] No name, DNA Human IgG miR29b Indirect, C12 spacer 595.9 ±43.1 Mucin-1 A549 cells in vitro [86] sgc8c and AS1411 Gold Daunorubicin Direct, covalent No data ALL and nucleolin Molt-4 cells in vitro [87] No name, RNA Gold Antisense ONT Spacer, covalent <50 CD33, CD34 AML-M2 in vitro [88] No name, DNA Mesoporous silica Doxorubicin Direct, covalent 181 ± 6 EpCAM SW620 colon cancer cells in vitro [89] TSA14, RNA PEGylated-liposome Doxorubicin Direct, covalent 118 ± 2.2 TUBO cells Breast cancer in vitro + in vivo [90] DNA-RNA hybrid SPION Doxorubicin DNA linker, streptavidin-biotin No data PSMA Prostate cancer in vitro [91] AS1411, DNA GC-rich dsDNA Doxorubicin Direct, covalent 6.1 ± 0.7; 7.4 ± 0.4 Nucleolin Drug-resistant MCF-7 cells in vitro [92] AS1411, DNA PEG-PLGA Gemcitabine Direct, covalent 128 ± 5.23 Nucleolin A549 cells in vitro [93] AS1411, DNA HPAEG Doxorubicin Direct, covalent 93.7 Nucleolin MCF-7 and L929 cells in vitro [94] No name, DNA DNA dendrimer Epirubicin No data 36.4 MUC1, AS1411 MCF-7 and C26 cells in vitro + in vivo [95] A10, RNA PLGA Triplex forming oligonucleotide Direct, covalent No data PSMA LNCaP cells in vitro [96] No name, RNA PLGA-PEG Docetaxel Direct, covalent 93.6 PSMA LNCaP cells in vitro + in vivo [97] AS1411, DNA M-PLGA–TPGS Docetaxel Direct, covalent 130.1 ± 2.9 Nucleolin HeLa cells in vitro + in vivo [98] Endo28, DNA 3WJ-RNA Doxorubicin Direct, covalent 8.1 ± 1.5 Annexin A2 Ovarian cancer in vitro + in vivo [99] No name, DNA HAS-CS Paclitaxel Acrylate spacer 170 ± 4 Mucin-1 MCF-7 and T47D cells in vitro [100] AS1411, DNA PEG-PAMAM dendrimer 5-fluorouracil Covalent, to PEG No data Nucleolin Gastric cancer in vitro [101] Two, DNA DGL-PEG Doxorubicin ATP-aptamer Covalent, to PEG ≈38 Nucleolin, Cyt c Nucleolin+ HeLa cells in vitro + in vivo [102] No name, DNA Iron oxide None (HTT) No data No data FGFR1 Human osteosarcoma in vitro [103] A10, RNA Liposome CRISPR-Cas9 plasmid Covalent, to DSPE-PEG ≈150 PSMA Prostate cancer in vitro + in vivo [104] AS1411, DNA PEG-PAMAM dendrimer Camptothecin Covalent, to PEG ≈18 Nucleolin HT29 and C26 cells in vitro + in vivo [105] A6, DNA Lipid-polymer liposome siRNA Direct, covalent 270 ± 10; 237 ± 12 HER2 SKBR-3 and 4T1-R cells in vitro [106] No name, DNA Chitosan- liposome Erlotinib Direct, covalent 179.4 ± 1.16 EGFR EGFR-mutated cancer cells in vitro [107] AS42, DNA Gold None (PTT) No data ≈37 Ehrlich’s ACC Ehrlich carcinoma in vivo [108] No name, DNA MCS nanogel Doxorubicin Direct, covalent 15–25 LNCaP cell Prostate cancer in vitro [109] AS1411 + S2.2, DNA Gold-coated liposome Docetaxel through S-Au bond ≈200 Mucin-1, Nucleolin MCF-7 cells in vitro + in vivo [110] 5TR1, DNA PLGA-chitosan Epirubicin Electrostatic coupling ≈222.7 Mucin-1 MCF-7 and C26 cells in vitro + in vivo [111] AS1411, DNA Alkyl PAMAM dendrimer Bcl-xL shRNA Covalent and non-covalent 148–230 Nucleolin A549 cells in vitro [112] Gint4.T PLGA-PEG-COOH PI3K-mTOR inhibitor Direct, covalent 52 ± 1 PGFRβ Glioblastoma U87MG cells in vitro + in vivo [113] No name, DNA Mesoporous silica Epirubicin Via disulfide bonding 258.5 ± 20.1 Mucin-1 MCF-7 cells in vitro [114] No name, DNA Aminopropyl MSN Safranin O electrostatic + H-bonding ≈407 Mucin-1 MDA-MB-231 cells in vitro [115] No name, DNA Chitosan- liposome PFOB and Erlotinib Direct, covalent ≈180 EGFR NSCLC cell lines in vitro + in vivo [116] No name, DNA Au-Fe3O4 None Electrostatic absorption 46 ± 3 VEGF SKOV-3 ovarian cancer cells in vitro [117] No name, DNA MPC-PAA/PEI Doxorubicin Anchoring via EHH No data Mucin-1 A549 and MCF-7 cells in vitro [118] A15, RNA PLGA Propranolol Direct, covalent 143.7± 24.6 CD133 Hemangioma in vitro + in vivo [119] AIR-3A, RNA PEG-coated gold NP None Thiol–gold bonds 2, 7, 36 IL-6R IL-6R-carrying cells in vitro [120] No name, DNA PDA/PEG- coated MSN DM1 Direct, covalent 203.75 ±2.37 EpCAM Colorectal cancer in vitro + in vivo [121] AS-14, DNA Gold-coated magnetic NP None, using magnetic field Thiolated ONT primer 50 (GMNP) Fibronectin protein Ehrlich carcinoma in vivo [122] AS1411, DNA Chitosan-ss-PEEUA TLR4-siRNA, Doxorubicin Direct, covalent 124.6 ± 1.068 Nucleolin A549 cells in vitro + in vivo [123] FKN-S2, DNA PEG-aptamer micelle None or Aptamer ssDNA-amphiphile No data Fractalkine Colon adeno-carcinoma in vitro + in vivo [124] No name, DNA Ursolic acid, Doxorubicin Ursolic acid, Doxorubicin Electrostatic interactions ≈108.9 HER2 HER2-carrying cells in vitro + in vivo [125] No name, DNA PEG-SPION Doxorubicin Direct, covalent 5–64 Mucin-1 MCF-7 cells in vitro [126] Two, DNA NMOF Doxorubicin Hybridization ≈130 Nucleolin, VEGF MDA-MB-231 in vitro [127] 5TR1, DNA PEI-PEG and Na2SeO3 Epirubicin and an aptamer Covalent, to PEG No data Mucin-1 MCF-7 and C26 cells in vitro + in vivo [128] No name, DNA Liposome Doxorubicin Amino- carboxyl 170 ± 25 HER3 MCF-7 breast cancer cells in vitro + in vivo [129] No name, DNA DNA nano-ring Doxorubicin Incorporated in DNA ring ≈29 (DNA ring) Mucin-1 MCF-7 breast cancer cells in vitro [130] A10–3.2, RNA Cationic nanobubble FoxM1 siRNA Direct, covalent 479.83 ± 24.50 PSMA LNCaP cells in vitro + in vivo [131] No name, DNA DNA micelle Doxorubicin, KLA peptide No data 371 Mucin-1 MCF-7 cells in vitro + in vivo [132] No name, DNA Lipid-polymer Salinomycin Thiolated, direct 96.3 ± 9.8 CD20 Melanoma stem cells in vitro + in vivo [133] No name, RNA Polymer-lipid Salinomycin Thiolated, direct 95 EGFR Osteosarcoma CSCs in vitro [134] trCLN3, DNA Lipidated GC-rich DNA hairpin Doxorubicin, 2′,6′-dimethyl azobenzene Lipid-mediated self-assembly 21.2 ± 1.5 cMet cMet-expressing H1838 cells in vitro [135] TLS1c, DNA Liposome Cabazitaxel Avidin-biotin interaction 90.10 ± 2.71 MEAR cells Hepatoma in vitro + in vivo [136] No name, DNA PBABT Docetaxel Direct, covalent 274.7 ± 46.1 HER2 Epithelixal ovarian cancer in vitro + in vivo [137] No name, DNA BSA-PEG-Fe3+ Mn, Doxorubicin GAG-linker, base-match No data Glut-1 HepG-2 cells in vitro + in vivo [138] AS1411 TD-PEC- chitosan miR-145 Electrostatic bonds with chitosan 40–270 Nucleolin MCF-7 cells in vitro + in vivo [139] No name, DNA DNA ALK-siRNA, Doxorubicin Direct, covalent 59 CD30 ALCL in vitro + in vivo [140] No name, DNA Human IgG MicroRNA Direct, covalent 595 Mucin-1 Non-small cell lung cancer in vitro + in vivo [141] S15, DNA Quantum dots None Direct, covalent No data NSCLC A549 cells in vitro [142] A15, CL4; RNA Lipid-polymer Salinomycin Direct, covalent 110.2 ± 12.1 CD133, EGFR Osteosarcoma cells and CSCs in vitro + in vivo [143] No name, DNA PEG-Au- PAMAM Curcumin Covalent, C6 linker 5.23 ± 4.12 Mucin-1 HT29 and C26 cells in vitro + in vivo [144] No name, RNA Liposome Docetaxel Covalent, to DSPE-PEG 116.5 ± 9.3 CD133 A549 cells in vitro + in vivo [145] 5TR1, DNA PEGylated liposome Doxorubicin No data 120 ± 1.8 Mucin1 C26 cells in vitro + in vivo [146] AS1411, DNA Bovine serum albumin Doxorubicin Direct, amidation 163 ± 2.5 Nucleolin MCF-7 cells in vitro [147] No name, DNA Copper oxide mRNA 29b Direct, amide linking ≈40 Mucin 1 A549 cells in vitro [148] Sgc8c, DNA Fe3O4-carbon Doxorubicin Direct, covalent No data No data A549 cells in vitro + in vivo [149] A9, RNA Gold None (PTT) No data ≈70 PSMA LNCaP cells in vitro [150] No name, DNA Gold nanoshell None (PTT) Direct, thiol–Au bonds No data Mucin 1 A549, MCF-7 3D cell culture in vitro [151] C10.36, DNA PAM (peptide + DNA ONT) Peptide Base pairing 110 ± 30 HBLL B-cell leukemia cells in vitro [152] No name, RNA LP-DNA SATB1 siRNA Thiolated, direct 161.2 ± 11.3 EGFR Choriocarcinoma in vivo [153] AS1411, DNA PEGylated PLGA anti-miR-21, cisplatin (CIS) Direct, covalent 142.4 ± 5.9 106.6 ± 5.9 Nucleolin CIS-resistant A2780 cells in vitro [154] No name, RNA Lipid-PLGA All-trans retinoic acid Thiolated, direct 129.9 CD133 Lung cancer initiating cells in vitro [155] S15, DNA PEG-PCL Paclitaxel Direct, amide linking ≈15 NSCLC A549 cells in vitro [156] S2.2, DNA Elastin-like polypeptide Paclitaxel Via gene A’ protein No data Mucin-1 MCF-7 cells in vitro [157] 5TR1, DNA PβAE and PLGA Epirubicin, antimir-21 Direct, covalent 210.4 ±10.14 Mucin-1 MCF-7 cells in vitro + in vivo [158] No name, RNA Lipid-polymer All-trans retinoic acid Thiolated, direct 129.9 CD133 Osteosarcoma initiating cells in vitro [159] No name, DNA Calcium carbonate Epirubicin, and melittin Avidin-biotin interaction >300 Mucin-1 MCF-7 and C26 cells in vitro + in vivo [160] ACE4 Diacetylene-PEG None 31 G spacer, base pairing ≈13 Annexin A2 MCF-7 cells in vitro [161] No name, DNA Human IgG Genistein and miRNA-29b C12 spacer, covalent 598 ± 34.1 Mucin-1 A549 cell line in vitro [162] No name, DNA Lipid-quantum dot siRNA Direct, covalent No data EGFR Triple-negative breast cancer in vitro + in vivo [163] HB5, DNA Human serum albumin Curcumin Direct, covalent 281.1 ± 11.1 HER2 SK-BR-3 cells in vitro [164] AS1411, DNA Magnetic SPION/MSN Doxorubicin Direct, covalent 89 Nucleolin MCF-7 cells in vitro [165] AS1411, DNA Albumin-IONP/GNP Doxorubicin Direct, covalent ≈120 Nucleolin MCF-7 and SKBR3 cells in vitro [166] C2NP, DNA PEG-PLGA Doxorubicin Direct, covalent 168.07 ± 2.72 CD30 Large cell lymphoma in vitro [167] AS1411, DNA Liposome Paclitaxel and PLK1 siRNA DSPE-PEG-MAL 121.27 ± 2.51 Nucleolin MCF-7 cells in vitro + in vivo [168] AS1411, DNA Liposome Aptamer- doxorubicin Not Applicable ≈128.6 Nuclear nucleolin MCF-7/Adr cells in vitro [169] AS1411, DNA PEGylated liposome 5-fluorouracil Via PEG linker 190 ± 15 Nuclear nucleolin Basal cell carcinoma in vitro [170] HApt, DNA β-CD-capped MSN Doxorubicin Thiolated to β-CD 218.2 ±6.1 HER2 HER2-positive cells in vitro [16] AS1411, DNA SPION Daunomycin, TMPyP Amide bond, direct 15–20 Nucleolin A549 and C26 cells in vitro [171] S1.5, DNA PEGylated PLGA Docetaxel Carbodiimide coupling 142.7± 12.3 HPA TNBC cells in vitro + in vivo [172] No name, DNA Mesoporous MnO2 HMME Direct, covalent ≈200 Mucin 1 MCF-7 cells in vitro + in vivo [173] AS1411, DNA PLGA, PVP Doxorubicin Direct, covalent ≈87.168 Nucleolin A549 cells in vitro + in vivo [174] No name, DNA DNA hydrogel CpG ONT and Doxorubicin Covalent, to CpG ONT 50.1 ± 2.82 Mucin-1 MCF-7 cells in vitro [175] AS1411, DNA; (HA) Micro-emulsion Shikonin and docetaxel Direct, thiolated ≈30 Nucleolin; (CD44) Glioma in vitro, model [176] No name, DNA Cationic liposome miR-139–5p Direct, covalent 150.3 ±8.8 EpCAM Colorectal Cancer in vitro + in vivo [177] Sgc8, DNA MSN Doxorubicin Direct, covalent 103.24  PTK7 CCRF-CEM cells in vitro [178] GMT8, Gint4.T; DNA DNA Paclitaxel Direct, covalent 17.78 U87MG cell, PDGFRβ Glioblastoma in vitro [179] AS1411, DNA Derived from erythrocytes Doxorubicin, siRNA Covalent to cholesterol via 6-A bases ≈100 Nucleolin MDR MCF-7 cells in vitro [180] TA6, DNA DNA nanotrain AKT inhibitor, Doxorubicin Direct, covalent No data CD44 Breast cancer stem cells in vitro + in vivo [181] A15, RNA Liposome Curcumin Direct, thiol-maleimide 86.6 ± 4.5 CD133 DU145 cells in vitro + in vivo [182] AS1411, DNA Silver-PEG None (irradiation) Amide bond to PEG 18.82 ± 2.1 Nucleolin Glioma in vitro + in vivo [183] U2, DNA Gold None Direct, Au-S bond ≈60.23 EGFR Glioblastoma in vitro + in vivo [184] M49, DNA PEGylated liposome Doxorubicin Covalent, to PEG No data CD200R1 4THM breast carcinoma in vivo [185] TC01, Sgc4f, and Sgc8; DNA DNA ONT Doxorubicin DNA ONT hybridization No data Multiple cancers and PTK7 CCRF-CEM cells in vitro + in vivo [186] No name, DNA DNA origami Antisense ONT, doxorubicin Extended sequences 4.17 ± 0.12 (height) Mucin-1 HeLa/ADR cells in vitro [187] LZH5B, DNA DNA nanotrain Doxorubicin Hybridization No data HepG2 cell HepG2 cell line in vitro [188] No name, DNA SPION@SiO2 Doxorubicin Direct, covalent 5–27  Mucin-1 MCF-7 cells in vitro [189] AS1411, DNA Upconversion nanoparticle Protoporphyrin IX Direct, covalent 120 ± 4 Nucleolin HeLa and A549 cells in vitro [190] AS-14, AS-42; DNA SPMFN Doxorubicin Glycosidic linkages No data FN, HSP71 Ehrlich carcinoma cells in vitro + in vivo [191] AS1411, DNA Gold Anti-miR-155 PolyA linker sequence ≈30 Nucleolin MCF-7 cells in vitro [192] L5, etc., DNA PLGA Docetaxel Direct, covalent 156.9 ± 42.97 Not clear yet HepG2 and Huh-7 cells in vitro + in vivo [193] L5, DNA PLGA Docetaxel Direct, covalent 211.9–236.1 TAG-72 HepG2 and Huh-7 cells in vitro [194] LXL, DNA RNA hydrogel siRNA and miRNA No data ≈200 MDA-MB-231 cell Triple-negative breast cancer in vitro + in vivo [195] AS1411, DNA CaCO3 and protamine CRISPR-Cas9 plasmid Covalent, to HA 230–320 Nucleolin H1299 cells in vitro [196] No name, RNA Hollow gold nanosphere Doxorubicin Thiolated ≈42 (25–55) CD30 Karpas 299 cells in vitro [197] C2NP, DNA DNA nanotube Doxorubicin By extending staples 140 × 14 (L × W) CD30 K299 cells in vitro [198] No name, DNA ssDNA-ELP Docetaxel Covalent, to ELP 10–40 Mucin-1 MCF-7 cells in vitro [199] No name, DNA Magnetic nanosphere Doxorubicin Streptavidin-biotin No data EpCAM MCF-7 cells (CTCs) in vitro [200] AS1411, DNA DNA nanotrains DOX, EPI, and DAU Base pairing No data Nucleolin HeLa cells in vitro [201] No name, RNA Protamine Doxorubicin, ALK-siRNA Non-covalent No data CD30 ALCL in vitro [202] AS1411, DNA TiO2 nanofiber with BSA None Streptavidin-biotin 81.33 ± 25.70 AS1411, DNA MCF-7 cells (CTCs) in vitro [203] AS1411, DNA Gold and liposome Morin Covalent, Au-S No data Nucleolin SGC-7901 cells in vitro + in vivo [204] AS1411, DNA GO Nanosheet Berberine derivative NH2-(CH2)6 linker 30–50 × 2–3 Nucleolin A549 cells in vitro [205] AS1411, DNA DNA Holliday junction Doxorubicin Phospho-diester bond 12.45 ± 2.16 Nucleolin CT26 colon cancer cells in vitro [206] Syl3c, DNA PEGylated liposome Doxorubicin Covalent, to PEG 110 ± 5 EpCam C26 Colon Carcinoma in vitro + in vivo [207] No name, DNA Ag-MOF-RBCm PFK15 Inserted into RBCm ≈109 CD20 B-cell lymphoma in vitro + in vivo [208] No name, DNA PCL-MMA/MPEG-MASI Doxorubicin Covalent, to NHS group ≈124 EpCAM HT29 cells in vitro [209] AS1411, DNA FO-loaded MOF-RBCm Using PDT and CDT effects Inserted via cholesterol 110–140 Nucleolin KB cells in vitro + in vivo [210] MAGE-A3, DNA NIR PLN Afatinib By a disulfide bond 225 MAGE NSCLC in vitro + in vivo [211] A10-3.2, RNA Lipid-polymer hybrid Curcumin and Cabazitaxel Covalent, to PEG 121.3 ± 4.2 PSMA Prostate cancer in vitro + in vivo [212] A6, DNA DOTAP, Mal-PEG, cholesterol, PLGA P-gp siRNA Covalent, to Mal-PEG No data HER2 DOX-resistant 4T1 cells in vitro [213] Wy5a, DNA PLGA-PEG-COOH Docetaxel Amide bond with spacer ≈154.3 PC-3 cell Prostate cancer in vitro + in vivo [214] The aptamers in the table are listed in the order they appear in the literature. ⱡ Size of the nanoparticles after aptamer conjugation. For spherical nanoparticle, the number is the diameter of the particle; for nanotubes or nanosheets, the measurement uses a × symbol. # Direct conjugation means there is no bridge, spacer, or linker molecule/sequence between the aptamer and the nanoparticle. * The aptamer-conjugated gold nanorods were surface modified with BSA through electrostatic interactions. ijms-21-09123-t002_Table 2Table 2 Aptamer-functionalized nanoparticles classified by nanomaterials and payloads. Type of Nanoparticle Payloads Aptamers Targets Cancers References Polymer based nanoparticles PLA-PEG Rhodamine-labeled dextran A10 PSMA Prostate cancer, [18] PLGA-PEG Cisplatin, Docetaxel, Doxorubicin, Gemcitabine, Paclitaxel, Salinomycin, Vinorelbine, PI3K-mTOR inhibitor, anti-miR-21, and cisplatin, A10, A15, AS1411, C2NP, EpCAM-Ap, Gint4.T, PSMA-Ap, S1.5, Wy5a CD30, CD133, EpCAM, HPA, Nucleolin, PC-3 cell, PGFRβ, PSMA Breast cancer, glioblastoma, glioma, large cell lymphoma, lung cancer, NSCLC, osteosarcoma, cisplatin-resistant ovarian cancer, prostate cancer, TNBC [22,29,35,57,71,76,81,102,6,122,163,176,181,223] PLGA Docetaxel, Paclitaxel, Nutlin-3a, Salinomycin, Triplex forming oligonucleotide, Propranolol A10, A15, AS1411, L5, S2.2, EpCAM-Ap PSMA, CD133, EGFR, MUC1, Nucleolin, TAG-72 Breast cancer, hepatocellular carcinoma, hemangioma, human glial cancer, prostate cancer [34,42,83,105,128,203] PEG-PCL Docetaxel AS1411, GMT8, S15 Nucleolin, NSCLC, U87 cells Glioblastoma, glioma, lung cancer [43,45,165] H40-PLA-PEG Doxorubicin A10 PSMA Prostate cancer [42] pPEGMA-PCL-pPEGMA Doxorubicin AS1411 Nucleolin Pancreatic carcinoma [52] PEG-PAMAM MicroRNA A10–3.2 PSMA Prostate cancer [58] PF127-β-CD-PEG-PLA Doxorubicin AS1411 Nucleolin Breast cancer [60] PEI EpCAM-siRNA EpCAM-Ap EpCAM Breast cancer, retinoblastoma [63] GPN Gefitinib Ets1-Ap Ets1 NSCLC [69] PLL-alkyl-PEI shRNA AS1411 Nucleolin Lung cancer [80] HPAEG Doxorubicin AS1411 Nucleolin Breast cancer [94] M-PLGA–TPGS Docetaxel AS1411 Nucleolin Cervical cancer [98] PBABT Docetaxel HER2-Ap HER2 Ovarian cancer [137] PβAE and PLGA Epirubicin and antimir-21 5TR1 MUC1 Breast cancer [158] PLGA, PVP Doxorubicin AS1411 Nucleolin Lung cancer [174] PCL-MMA/MPEG-MASI Doxorubicin EpCAM-Ap EpCAM Colorectal cancer [209] Lipid based nanoparticles Liposome Curcumin, Doxorubicin, Cabazitaxel, Cisplatin, CRISPR-Cas9 plasmid, Docetaxel, Doxorubicin, Paclitaxel, and PLK1 siRNA, TSP A10, A15, AS1411, HER3-Ap, PSMA-Ap, TLS1c CD133, HER3, MEAR cells, Nucleolin, PSMA, PDGFR Breast cancer, DOX-resistant breast cancer, Hepatoma, lung cancer, prostate cancer, [33,50,58,65,113,138,145,154,178,191] PEGylated-liposome 5-FU, Doxorubicin, Anti-BRAF siRNA 5TR1, AS1411, M49, Syl3c, TSA14, CD200R1, EpCAM, Mucin1, Nucleolin, TUBO cells Basal cell carcinoma, breast cancer, colon carcinoma, melanoma [50,90,146,170,185,207] DOTAP:DOPE liposome Doxorubicin SRZ1 4T1 cells Breast cancer [76] Cationic liposome miR-139–5p EpCAM-Ap EpCAM Colorectal Cancer [177] Chitosan based nanoparticles Chitosan SN38 MUC1-Ap MUC1 Colon cancer [55] Chitosan and HA SN38 MUC1-Ap MUC1 Colorectal adenocarcinoma [78] HAS-CS Paclitaxel MUC1-Ap MUC1 Breast cancer [100] Dendrimer based nanoparticles Dendrimer MicroRNA S6, sgc8c A549 cell, CCRF-CEM ALL, NSCLC [23,79] ONT-PAMAM dendrimer Doxorubicin A9 PSMA Prostate cancer [29] PEG-PAMAM dendrimer 5-fluorouracil, Camptothecin AS1411 Nucleolin Colorectal cancer, Gastric cancer [101,105] DGL-PEG Doxorubicin, ATP-aptamer AS1411, Cyt c-Ap Nucleolin, Cyt c Cervical cancer [102] Alkyl PAMAM dendrimer Bcl-xL shRNA AS1411 Nucleolin Lung cancer [112] Hydrogel based nanoparticles MCS nanogel Doxorubicin LNCaP-Ap LNCaP cell Prostate cancer [109] DNA Hydrogel CpG ONT and Doxorubicin MUC1-Ap MUC1 Breast cancer [175] RNA Hydrogel siRNA and miRNA LXL MDA-MB-231 cell Triple-negative breast cancer [195] Nucleic acid based nanoparticles DNA icosahedra Doxorubicin MUC1-Ap MUC1 Breast cancer [27] Aptamer DNA Antisense ONT against P-gp sgc8c CCRF-CEM cell ALL [45] GC-rich dsDNA Doxorubicin AS1411 Nucleolin Drug-resistant breast cancer [92] DNA dendrimer Epirubicin MUC1-Ap, AS1411-Ap MUC1, AS1411 Breast and colon cancers [95] 3WJ-RNA Doxorubicin Endo28 Annexin A2 Ovarian cancer [99] DNA nano-ring Doxorubicin MUC1-Ap MUC1 Breast cancer [130] Lipidated GC-rich DNA hairpin Doxorubicin and 2′,6′-dimethyl-azobenzene trCLN3 cMet cMet-expressing lung cancer [135] DNA ALK-siRNA, Doxorubicin, Paclitaxel CD30-Ap, Gint4.T, GMT8, Sgc4f, Sgc8, TC01 cancer cells, CD30, PDGFRβ, PTK7, U87MG cell ALCL, ALL, Glioblastoma [140,179,186] DNA origami Antisense ONT, doxorubicin MUC1-Ap MUC1 MDR cervical cancer [187] DNA nanotube Doxorubicin C2NP CD30 Human anaplastic large cell lymphoma [198] DNA nanotrain AKT inhibitor, DAU, DOX, DNR, EPI, Gold AS1411, LZH5B, Sgc8, TA6 CD44, HepG2 cell, nucleolin, PTK7 ALL, Breast cancer stem cell, cervical cancer, liver cancer [46,181,188,201] DNA Holliday junction Doxorubicin AS1411 Nucleolin Colon cancer [206] Protein/peptide based nanoparticles Albumin Cisplatin, Curcumin, Doxorubicin AS1411, EGFR-Ap, HB5 EGFR, HER2, nucleolin Breast cancer, cervical cancer [85,147,164] Human IgG Genistein, miRNA-29b MUC1-Ap MUC1 NSCLC [86,141,162] Elastin-like polypeptide Paclitaxel S2.2 MUC1 Breast cancer [157] Human serum albumin Protamine Doxorubicin, ALK-siRNA CD30-Ap CD30 Lymphoma [202] Polymer and lipid hybrids PLGA-lecithin-PEG Paclitaxel, Curcumin AS1411, EpCAM Nucleolin Breast cancer, colorectal adenocarcinoma [32,51] PLGA-lipid-PEG Docetaxel XEO2mini PC3 cells Prostate cancer [31] Lipid-polymer liposome siRNA A6 HER2 Breast cancer [106] Polymer-lipid All-trans retinoic acid, Curcumin and Cabazitaxel, Salinomycin A10–3.2, A15, CD20-Ap, CD133-Ap, CL4, EGFR-Ap CD20, CD133, EGFR, PSMA Melanoma, osteosarcoma, prostate cancer [133,134,143,159,212] Lipid-PLGA All-trans retinoic acid CD133-Ap CD133 Lung cancer [155] DOTAP, PLGA, cholesterol, Mal-PEG P-gp siRNA A6 HER2 DOX-resistant breast cancer [213] Polymer and chitosan hybrids PLGA-chitosan Epirubicin 5TR1 MUC1 Breast cancer, colon carcinoma [111] Chitosan-ss-PEEUA TLR4-siRNA, Doxorubicin AS1411 Nucleolin Lung cancer [123] Chitosan and lipid hybrids Chitosan-liposome Erlotinib EGFR-Ap EGFR EGFR-mutated cancer cells [107] Chitosan-liposome PFOB and Erlotinib EGFR-Ap EGFR NSCLC [116] Nucleic acid and peptide hybrids KLA-DNA micelle Doxorubicin+KLA MUC1-Ap MUC1 Breast cancer [132] PAM (peptide +DNA ON) Peptide C10.36 HBLL B-cell leukemia [152] ssDNA-ELP Docetaxel MUC1-Ap MUC1 Breast cancer [199] Other organic nanoparticles Atelocollagen MicroRNA A10–3.2 PSMA Prostate cancer [59] Tocopheryl PEG-PβAE Docetaxel AS1411 Nucleolin Ovarian cancer [77] PEG-aptamer micelle None or Aptamer FKN-S2 Fractalkine Colon adeno-carcinoma [124] Ursolic acid Doxorubicin HER2-Ap HER2 HER2-carrying cells [125] TD-PEC-chitosan miR-145 AS1411 Nucleolin Breast cancer [139] LP-DNA SATB1 siRNA EGFR-Ap EGFR Choriocarcinoma [153] Diacetylene-PEG None ACE4 Annexin A2 Breast cancer [161] Inorganic nanoparticles Au-Ag Photothermal therapy sgc8c CCRF-CEM cell ALL [21] Gold Anti-miR-155, Antisense ONT, Daunorubicin, Doxorubicin, TMPyP4, PTT A9, AIR-3A, AS1411, As42, CD30-Ap, CD33/CD34-Ap, KW16–13, MUC1-Ap, sgc8c, U2 CCRF-CEM, CD30, CD33/CD34, EGFR, Ehrlich’s ACC, IL-6R, MCF10CA1h, MUC1, nucleolin, PSMA ALL, AML, breast cancer, cervical cancer, Ehrlich carcinoma, glioblastoma, human breast duct carcinoma, lymphoma, lung cancer, prostate cancer [15,44,53,54,66,82,87,88,108,120,150,151,184,192,197] Mesoporous silica Doxorubicin, Epirubicin, Fluorescein, gold nanorods AS1411, Sgc8, EpCAM-Ap, MUC1-Ap Nucleolin, PTK7, EpCAM, MUC1 ALL, breast cancer, human T cell leukemia, colon cancer [35,38,39,40,89,114,178] Mesoporous silica–carbon Doxorubicin HB5 HER2 Breast cancer [64] Graphene oxide-gold Doxorubicin, None (PTT) S2.2, MUC1-Ap MUC1 Breast cancer, lung cancer [65,73] Graphene oxide-MSN Doxorubicin Cy5.5-AS1411 Nucleolin Breast cancer [71] ZnO Doxorubicin S2.2 MUC1 Breast cancer [75] GQD-FMSN Doxorubicin AS1411 Nucleolin Cervical cancer [81] Iron None (HTT) MA3 MUC1 Breast cancer [84] Au-Fe3O4 None VEGF-Ap VEGF Ovarian cancer [117] Copper oxide mRNA 29b MUC1-Ap MUC1 Lung cancer [148] Calcium carbonate Epirubicin, and melittin MUC1-Ap MUC1 Breast cancer [160] Mesoporous MnO2 HMME MUC1-Ap MUC1 Breast cancer [173] Silver-PEG Irradiation AS1411 Nucleolin Glioma [183] Graphene oxide sheets Berberine derivative AS1411 Nucleolin Lung cancer [205] Quantum dot based nanoparticles Quantum dots None S15 NSCLC Lung cancer [142] QD-PMAT-PEI siRNA PSMA-Ap PSMA Prostate cancer [30] Lipid-quantum dot siRNA EGFR-Ap EGFR Triple-negative breast cancer [163] Magnetic nanoparticles SPION Epirubicin, Doxorubicin, Daunomycin and TMPyP 5TR1, A9, A10, AS1411, DNA-RNA hybrid MUC1, Nucleolin, PSMA Colon cancer, breast cancer, lung cancer, prostate cancer [22,28,43,91,171] Dextran-ferric oxide None HER2-Ap HER2 Human adenocarcinoma [47] Au-SPION None MUC1-Ap MUC1 Colon cancer [83] Iron oxide None (HTT) FGFR1-Ap FGFR1 Human osteosarcoma [103] Gold-coated magnetic NP None AS-14 Fibronectin protein Ehrlich carcinoma [122] PEG-SPION Doxorubicin MUC1-Ap MUC1 Breast cancer [126] Fe3O4-carbon Doxorubicin Sgc8c-Ap Sgc8c Lung cancer [149] Magnetic SPION/MSN Doxorubicin AS1411 Nucleolin Breast cancer [165] SPMFN Doxorubicin AS-14 and AS-42 FN and HSP71 Ehrlich carcinoma [191] SPION@SiO2 Doxorubicin MUC1-Ap MUC1 Breast cancer [189] Magnetic nanosphere Doxorubicin EpCAM-Ap EpCAM Breast cancer [200] Other inorganic nanoparticles Gd:SrHap Doxorubicin AS1411 Nucleolin Breast cancer [37] Organic and inorganic hybrids MOF-UCNP Doxorubicin AS1411 Nucleolin Breast cancer [68] Gold-liposome Docetaxel, Morin AS1411, S2.2 Nucleolin, MUC1 Breast cancer, gastric cancer [119,213] Aminopropyl MSN Safranin O MUC1-Ap MUC1 Breast cancer [115] MPC-PAA/PEI Doxorubicin MUC1-Ap MUC1 Breast cancer, lung cancer [118] PDA/PEG- coated MSN DM1 EpCAM-Ap EpCAM Colorectal cancer [121] NMOF Doxorubicin AS1411, VEGF-Ap Nucleolin, VEGF Breast cancer [127] PEI-PEG and Na2SeO3 Epirubicin and an aptamer 5TR1 MUC1 Breast cancer [128] BSA-PEG-Fe3+ Mn, Doxorubicin Glut-1-Ap Glut-1 Liver cancer [138] PEG-Au- PAMAM Curcumin MUC1-Ap MUC1 Colon adenocarcinoma [144] Albumin-IONP/GNP Doxorubicin AS1411 Nucleolin Breast cancer [166] β-CD-capped MSN Doxorubicin HApt HER2 HER2-positive cells [16] CaCO3 and protamine CRISPR-Cas9 plasmid AS1411 Nucleolin NSCLC [196] TiO2 nanofiber with BSA None AS1411 Nucleolin Breast cancer CTCs [203] Others Cationic nanobubble FoxM1 siRNA A10–3.2 PSMA Prostate cancer [131] Micro-emulsion Shikonin and docetaxel AS1411 and HA Nucleolin and CD44 Glioma [176] RBC membrane Doxorubicin, siRNA AS1411 Nucleolin MDR breast cancer [180] Upconversion nanoparticle Protoporphyrin IX AS1411 Nucleolin Cervical cancer, lung cancer [190] Ag-MOF-RBCm Doxorubicin CD20-Ap CD20 B-cell lymphoma [208] FO-loaded MOF-RBCm Using PDT and CDT effects AS1411 Nucleolin KB Cell Line [210] NIR PLN Afatinib MAGE-A3 MAGE NSCLC [211] For aptamers that do not have a name, “target-Ap” is used to represent the aptamer; for example, EpCAM-Ap represents the aptamer that targets EpCAM. ==== Refs References 1. 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