Functional DNA Structures and Their Biomedical Applications

Abstract

Open AccessCCS ChemistryMINI REVIEW1 Oct 2020Functional DNA Structures and Their Biomedical Applications Ziyuan Li†, Chen Wang†, Jiang Li†, Junji Zhang, Chunhai Fan, Itamar Willner and He Tian Ziyuan Li† Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, East China University of Science & Technology, Shanghai 200237 (China) †Z. Li, C. Wang, and J. Li contributed equally to this work.Google Scholar More articles by this author , Chen Wang† Institute of Chemistry, The Minerva Center for Biohybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem 91904 (Israel) †Z. Li, C. Wang, and J. Li contributed equally to this work.Google Scholar More articles by this author , Jiang Li† Bioimaging Center, Shanghai Synchrotron Radiation Facility, Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210 (China) School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240 (China) †Z. Li, C. Wang, and J. Li contributed equally to this work.Google Scholar More articles by this author , Junji Zhang *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, East China University of Science & Technology, Shanghai 200237 (China) Google Scholar More articles by this author , Chunhai Fan School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240 (China) Google Scholar More articles by this author , Itamar Willner *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] Institute of Chemistry, The Minerva Center for Biohybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem 91904 (Israel) Google Scholar More articles by this author and He Tian Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, East China University of Science & Technology, Shanghai 200237 (China) Google Scholar More articles by this author https://doi.org/10.31635/ccschem.020.202000236 SectionsAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Since the discovery of the double-helix structure in 1953, nucleic acids have been developed from natural genetic codes into functional building blocks in a wide range of biotechnology and materials sciences. Taking advantage of their design diversity and biocompatibility, functional nucleic acids facilitate the “bottom-up” fabrication of nanomaterials that are highly potential for molecular medicine to treat different diseases, such as cancers. The present perspective article introduces recent advances in the use of these unique properties of nucleic acid biopolymers for biomedical applications. Specifically, nanomaterial/nucleic acid hybrid structures for sensing, controlled drug release, programmable intracellular imaging, and apoptosis, as well as logic calculation, are discussed. Furthermore, the detailed operation for both extracellular and intracellular bioactivity regulation with these new design functional nucleic acid nanostructures are fully illustrated. Download figure Download PowerPoint Introduction The base-sequence comprising nucleic acids provide substantial structural and functional information into their biopolymers.1 Some of these structural and functional motifs are summarized in Figure 1. The base pairing of complementary nucleic acids and the accompanying strand displacement process (a) represent one of the most fundamental features of DNA. The signal-triggered reconfigurations of nucleic acids, such as the pH-stimulated formation and dissociation of i-motif structures,2,3 (b) ,triplex assemblies, (c),4–6 or the reversible reconfiguration of K+-ions stabilized G-quadruplexes and their separation in the presence of crown ethers,7 (d), represent sequence-dictated reconfiguration process of nucleic acids. In addition, the cooperative stabilization of duplex nucleic acids by metal-ion bridging of base mismatches, for example, T-Hg2+-T or C-Ag+-C, and their separation by ion binding ligands, such as cysteine8–10 (e) demonstrate further the capabilities to control the structures and stabilities of nucleic acid assemblies. Functional information embedded in the nucleic acid biopolymers includes sequence-specific recognition and binding of molecular or macromolecular ligands (aptamers)11–13 (f), and sequence-controlled catalytic properties of nucleic acids, characteristic of DNAzymes14,15 or nucleoapzymes16, (g). Besides, a variety of enzymes control the structures of nucleic acids. These include nonspecific hydrolysis of the biopolymers by DNases (h), ligation of nucleic acid units by DNA ligase, or replication of template/probe duplexes by polymerase/dNTP (not shown), and sequence-specific degradation of duplex nucleic acids by endonucleases17,18 (i), exonucleases19,20 (j) or nicking enzymes21–24 (k). In addition to the signal-triggered reconfiguration of nucleic acid biopolymers, their self-assembly into two-dimensional (2D) and three-dimensional (3D) nanostructures are of fundamental interest. For example, the folding of a circular viral DNA into predesigned 2D origami nanostructures using stapler strands25–28 (l), the guided formation of interlocked, supramolecular DNA catenanes29 (m), or rotaxanes30–32 (n), the self-assembly of inter-hybridized nucleic acids into 3D structures, such as DNA tetrahedra33,34 (o), or balls35 (p), and the scaling of 2D origami systems into 3D nanostructures, for example, boxes36 (q), represent means to translate the information encoded in DNA to construct complex structures. These unique properties of nucleic acids provide the grounds for the development of an area of DNA nanotechnology, where the assembly of ingenious 2D and 3D DNA nanostructures,37–39 the application of nucleic acids as functional materials to construct switches40 and DNA machines,41–44 and the use of nucleic acids as active materials for sensing and imaging were demonstrated.45–47 Figure 1 | Structural and functional information encoded in DNA nanostructures: (a) strand displacement of duplex structures; (b) pH-stimulated random coil/i-motif reversible transitions; (c) pH-stimulated reversible reconfiguration of triplex nanostructures; (d) K+-ion/crown ether-stimulated formation and dissociation of G-quadruplexes; (e) metal–ion cooperative stabilization of duplex nucleic acids; (f) separation of nucleic acid duplexes via selective aptamer–ligand complexes; (g) catalytic functions of metal–ion-dependent DNAzymes; (h) DNase I-stimulated degradation of nucleic acids; (i) endonuclease-induced selective cleavage of duplex nucleic acids; (j) programmed stepwise 3’-end digestion of duplex nucleic acids by exonuclease III; (k) sequence-specific nicking of a duplex strand by a nicking enzyme; (l) self-assembly of stapled 2D origami nanostructures; (m) dynamic interlocked DNA catenane structure; (n) dynamic translocation of a DNA ring on a DNA-interlocked rotaxane assembly; (o) a DNA tetrahedron 3D structure; (p) a DNA buckyball 3D nanostructure; (q) the stepwise assembly of 2D origami tiles into 3D origami box. (a–d, f–k) Adapted with permission.96 Copyright 2018, American Chemical Society. (e) Adapted with permission.109 Copyright 2015, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (l) Adapted with permission.27 Copyright 2010, Royal Society of Chemistry. (m) Adapted with permission.29 Copyright 2016, American Chemical Society. (n) Adapted with permission.31 Copyright 2012, American Chemical Society. (o) Adapted with permission.147 Copyright 2018, American Chemical Society. (p) Adapted with permission.35 Copyright 2010, American Chemical Society. (q) Adapted with permission.95 Copyright 2017, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Download figure Download PowerPoint Nanotechnology has rendered nanomaterials with unique optical and electronic properties dominated by the size of the materials; these include metallic plasmonic nanoparticles/nanorods,48 semiconductor quantum dots (QDs),49,50 carbon nanotubes,51,52 and graphene/graphene oxides.53,54 The ability to modify the nanomaterials with molecular, macromolecular, or biomolecular components paves the way to prepare hybrid nanostructures that combine the unique properties of the nanomaterials with the functionalities of the chemical modifier units. Not surprisingly, the conjugation of nucleic acids to different kinds of nanomaterials yields hybrid nanostructures that combine the properties and functions of the coupled components. Indeed, nucleic-acid-functionalized nanomaterials have found widespread uses in sensing,55 imaging,56–58 and drug carriage for controlled release.59 In addition, the covalent tethering of nucleic acids to polymer matrices, for example, photoactive polymers,60–62 hydrogel-forming polymers,63 or metal–organic-framework particles,64 yields hybrid materials that combine the properties of the composite components. These materials have been applied in sensing,65 stimuli-responsive materials acting as shape-memory and self-healing matrices,66,67 and materials mimicking robotic functions.68 In the present article, we summarize several recent studies exemplifying the use of DNA nanostructures and hybrid nucleic acid nanostructures for biomedical applications. Specifically, the use of hybrid nucleic acids/nanomaterials for biomedical sensing and stimuli-triggered nanocarriers for controlled drug release will be described. In addition, the application of programmable nucleic acid nanostructures for intracellular logic operation, intracellular networks regulation, as well as theranostic applications are addressed. Nanoparticle-Functionalized Nucleic-Acid-Based Sensors and Drug Carriers DNA–nanoparticle hybrids for sensing An important topic in nanomedicine involves the application of nanomaterial/biomaterial hybrid systems for sensing applications.69–73 Many different approaches to apply enzyme/nanoparticle conjugates, antigen or antibody-modified nanoparticles or nucleic acid-functionalized nanoparticles have been applied broadly to develop electrochemical and photoelectrochemical-based sensors,55,74 optical/electrochemical immunosensors,75 and optical/electrochemical nucleic-acid-based sensors.76 Within the activities involving nucleic acid/nanomaterial hybrids for biomedical sensing applications, extensive efforts have been directed to the use of semiconductor QDs77,78 or silver nanoclusters (AgNCs)79 as optical transducers. Semiconductor QDs exhibit unique optical properties reflected by high-luminescence quantum yields, narrow-luminescence bands, large Stokes shifts, high stability, and particularly, size-controlled luminescent properties. The chemical approach to functionalize the surfaces of QDs with molecular or biomolecular units turns the biomolecule–QDs conjugates into ideal hybrids for sensing applications. Photophysical mechanisms involving fluorescence or fluorescence resonance energy transfer (FRET) are widely used to develop sensing platforms for medical diagnostic applications. Besides, nucleic-acid-stabilized metal nanoclusters (NCs) (consisting of 8–16 aggregated metal atoms) reveal unique optical and chemical functionalities for sensing applications.80 Different nucleic-acid-stabilized metal NCs, for example, AgNCs or AuNCs, reveal tunable luminescence properties, controlled by sequence-specific nucleic acid stabilizing the NCs and the degree of aggregation within the NCs. Moreover, the tethering of auxiliary strands to the sequence-specific nucleic acids stabilizing the NCs provides unique means to tailor recognition sites for the analytes in proximity to the luminescent optical transducers.81 The development of sensors should address two important issues: (i) the sensing matrices should allow a multiplexed analysis of different targets. In this context, the size-controlled luminescence properties of QDs or the variable composition-controlled luminescence properties of nucleic acid-stabilized metal NCs allow the assembly of multi-composite QDs or NCs hybrid systems for multiplexed analysis. (ii) The sensing platforms should include an amplification path to enhance the sensitivity of the sensing platforms. In this context, the coupling of catalysts, such as DNAzymes,82,83 DNA machineries,84,85 or the coupling of mechanisms to regenerate the analytes86,87 provides versatile methods to amplify the primary recognition events. The multiplexed analysis of genes by different-sized CdSe/ZnS QDs using the chemiluminescent resonance energy transfer (CRET) mechanism88 is presented in Figure 2a. The hemin/G-quadruplex horseradish peroxidase (HRP)-mimicking enzyme catalyzes (similarly to the native HRP enzyme) the oxidation of luminol by H2O2 with the concomitant generation of chemiluminescence at 420 nm. This catalytic property was used to develop various sensing platforms using chemiluminescence as readout signals. In addition, it was found that the conjugation of the hemin/G-quadruplex to semiconductor QDs stimulates the CRET process to the QDs, where the light generated by the DNAzyme-catalyzed oxidation of luminol by H2O2 was used as the internal energy source to excite the QDs, leading to the luminescence of the QDs. This CRET function of the hemin/G-quadruplex–QDs conjugates was then used to develop the CRET-based gene-sensing platforms. The semiconductor QDs, for example, luminescent at 620 nm, were functionalized with hairpin ( 1) that includes in its loop region the sequence recognizing the gene ( 2) and in the stem domain the caged sequence of G-quadruplex. In the presence of the gene ( 2), the hairpin structure was opened, leading to the self-assembly of the hemin/G-quadruplex to stimulate, in the presence of luminol/H2O2, the CRET-induced luminescence of the QDs at 620 nm. As the CRET signal is controlled by the concentration of the gene ( 2), this method allows the quantitative evaluation of the genes. By applying three different-sized QDs, emitting at 620, 560, and 490 nm, the multiplexed analysis of three different genes was demonstrated (Figure 2b). The different-sized QDs were modified with the hairpins ( 1), ( 3), and ( 5), respectively. The loop domains of the hairpins include the recognition sequences for the genes ( 2), ( 4), and ( 6), respectively, while all stem domains associated with the hairpins include the caged G-quadruplex sequences. Subjecting the mixture of QDs to any composition of the target genes, in the presence of luminol/H2O2 and hemin, resulted in the unlocking of the hairpin structures and the formation of the respective hemin/G-quadruplex conjugates that triggered the CRET process and the accompanying luminescence of respective genes. Figure 2e exemplifies the multiplexed analysis of three genes by the mixture of QDs. The concept of the hemin/G-quadruplex, CRET-driven sensing platforms in the presence of QDs was extended to other systems of biomedical diagnosis. For example, many aptamers reconfigure, in the presence of their ligands, into G-quadruplex aptamer/ligand complexes, for example, the antithrombin aptamer/thrombin complex. Accordingly, the thrombin aptamer was conjugated to CdSe/ZnS QDs emitting at 420 nm and the CRET-driven sensing was accomplished (Figure 2c).89 Figure 2 | (a) Chemiluminescence resonance energy transfer (CRET) within a semiconductor (CdSe/ZnS) quantum dot/hemin G-quadruplex conjugate. The hemin/G-quadruplex-catalyzed generation of chemiluminescence, in the presence of luminol/G-quadruplex, provides a localized internal light source for the excitation of QDs and the stimulation of QDs features. (b) A hairpin (1)/(3)/(5)-modified CdSe/ZnS QD for the CRET analysis of a gene (2)/(4)/(6). The hairpin includes in its stem region the caged G-quadruplex sequence, and in the loop region of the specific sequence for the recognition of (2)/(4)/(6). The opening of the hairpin activates the formation of the hemin/G-quadruplex and the accompanying CRET process. The intensity of the resulting CRET signal is controlled by the concentration of the gene. (c) Schematic configuration of the thrombin aptamer/QDs conjugate for the CRET analysis of thrombin. The formation of the G-quadruplex aptamer–thrombin complex/QDs conjugate leads to the CRET process, in the presence of hemin and luminol/H2O2. (d) Schematic amplified parallel analysis of two different genes (8) and (10) by two different-sized CdSe/ZnS QDs functionalized with probes (7) and (9) functionalized with BHQ-2, and BHQ-1, respectively, and using Exonuclease III (Exo III) as amplification catalyst for the regeneration of analytes. (e) CRET luminescence spectra corresponding to the multiplexes analysis of the genes (2), (4), (6) by the mixture of three different sized QDs modified by (1), (3), (5). (f)–(h) Time-dependent luminescence spectra of the mixture of (7)- and (9)-modified different-sized QDs upon analyzing: (f) analyte (8), (g) analyte (10), and (h) the mixture of analytes (8) and (10). Time-dependent spectra were recorded at 12 min time intervals. (a, b, e) Adapted with permission.88 Copyright 2011, American Chemical Society. (c) Adapted with permission.89 Copyright 2011, American Chemical Society. (d, f–h) Adapted with permission.90 Copyright 2011, American Chemical Society. Download figure Download PowerPoint The amplified and multiplexed analysis of genes using the QDs as the luminescence probes is exemplified in Figure 2d. The CdSe/ZnS QDs were modified with the gene recognizing strand ( 7) that was modified with a black-hole quencher (BHQ-2) at the 3’-end. This construct led to the quenching of the luminescence of the QDs.90 In the presence of the analyte gene ( 8) and coadded exonuclease III (Exo III), hybridization between ( 7) and ( 8) on the QDs proceeded with the accompanying Exo-III-induced cleavage (degradation) of the strand ( 7) of the duplex ( 7)/( 8), resulting in the release (regeneration) of the analyte gene ( 8). The cyclic regeneration of the analyte gene with the concomitant cleavage of the quencher units resulted in the increasing luminescence of the QDs and provided an amplification path for analyzing the genes. The amplified and multiplexed analysis of two genes using different-sized luminescent QDs (emitting at 540 and 620 nm) is displayed in Figure 2d. The two-sized QDs were functionalized with the quencher-modified strands ( 7) and ( 9) that recognized the genes ( 8) or ( 10), respectively, resulting in the quenching of the luminescence of the two-sized QDs. In the presence of any of the two genes, or the mixture of the two genes and coadded Exo III, the duplexes of the respective probe/gene ( 7)/( 8) and/or ( 9)/( 10) were formed, leading to the Exo-III-amplified switch-on of the luminescence of the respective QDs, Figure 2f–h. The use of luminescent nucleic-acid-stabilized AgNCs exhibiting sequence/size-controlled luminescence properties for sensing and multiplexed sensing of genes is presented in Figure 3. This is exemplified with the design of a hairpin scaffold HA ( 11), that included in its loop region I the recognition sequence of the BRAC1 gene. The stem domain of the hairpin was extended at its 3’- and 5’-ends with tethers II and III that were complementary to the II’-nucleic acid functionalized with the black-hole quencher (BHQ-2) and the III’-nucleic acid-protected AgNCs (six to seven atoms, luminescence at 615 nm). The mixture of these constituents led to the supramolecular hairpin structure, in which the close spatial proximity between the AgNCs and the black-hole quencher led to the effective quenching of the AgNCs. Subjecting the hairpin sensing scaffold to the BRAC1 gene ( 12), led to the opening of the hairpin structure that resulted in the spatial separation between the quencher and luminescent AgNCs. The hairpin scaffold enabled the analysis of the gene with a detection limit that corresponded to 9 nM. In addition, the tunable luminescence properties of the nucleic-acid-stabilized AgNCs were applied further for the multiplexed analysis of the BRAC1 gene and a second random strand T, as a gene model,91 using nucleic-acid-stabilized AgNCs, emitting at 540 and 615 nm (Figure 3a). The hairpin HA includes the sensing scaffold for analyzing the BRAC1, as outlined in Figure 3a. The hairpin HB, ( 13), included in its loop region IV the complementary recognition sequence for the gene model strand T, and the nucleic acid tethers conjugated to the 3’-end and 5’-end domains V and VI were complementary to the black-hole quencher-modified strand V’ and the luminescent AgNCs-protected nucleic acid VI’. The mixture of the two hairpins HA and HB allowed the multiplexed analysis of the two genes, Figure 3b. In the presence of the gene T, ( 14), the hairpin HB was opened, resulting in the intensified luminescence at the 540 nm of luminescent AgNCs. In the presence of the BRAC1 gene, ( 12), the hairpin HA was unlocked, leading to the selective enhanced luminescence of the 615 nm of luminescent AgNCs. In the presence of the two analytes, the two sensing hairpins were unlocked, leading to the enhanced luminescence of the 540 and 615 nm of luminescent NCs. Related nucleic-acid-protected AgNCs-based scaffolds were used for the multiplexed analysis of genes of biomedical significance, for example, the Werner Syndrome gene and the human immunodeficiency virus gene (HIV). Figure 3 | (a) Multiplexed analysis of the BRAC1 gene (12) and random strand T (14) using the hairpin HA (11) and HB (13) composed of the 615 nm luminescent Ag NCs and the 560 nm luminescence Ag NCs. (b) Fluorescence spectra changes upon the multiplexed analysis of the BRAC1 gene (12) and of random strand T (14) using the two Ag NCs/quencher modules according to (a): Panel I—analysis of random strand T (14), 5 × 10−6 M; Panel II—analysis of the BRAC1 gene (12), 1 × 10−6 M; Panel III—analysis of the two analytes (12) and (14), 1 × 10−6 M and 5 × 10−6 M, respectively. The system is excited at λ = 520 nm to record the 615 nm luminescence and at λ = 480 nm to follow the 560 nm luminescence. (c) Multiplexed analysis of the HBV gene (18) and of the HIV gene (17) using the near-infrared- and red-emitting Ag NCs probes. (d) Fluorescence spectra of the Ag NCs: (I) In the absence of the targets genes; (II) In the presence of gene (17); (III) In the presence of gene (18); (IV) In the presence of HIV gene (17) and HBV gene (18). Curves a and b correspond to the fluorescence of the red-emitting and the near-infrared-emitting Ag NCs, respectively. Fluorescence spectra were recorded after a fixed time interval of 80 min. (a and b) Adapted with permission.91 Copyright 2014, American Chemical Society. (c and d) Adapted with permission.92 Copyright 2013, American Chemical Society. Download figure Download PowerPoint In addition, the sequence/size-controlled luminescence properties of AgNCs were used for multiplexed analysis of genes or aptamer–ligand complexes through the coupling of AgNCs-functionalized probes to graphene oxide nanostructures92 (Figures 3c and 3d). These sensing platforms are based on the strong binding interaction of single-strand nucleic acids with graphene oxide and their dissociation from graphene surfaces upon the formation of duplex nucleic acids (Figure 3c). Accordingly, the strand ( 15), acting as a recognition sequence for the hepatitis B virus (HBV), was conjugated to the 615 nm luminescent AgNCs/DNA, and the strand ( 16), acting as the recognition sequence of HIV, was conjugated to the 775 nm luminescent Ag NCs/DNA. The two strands were deposited on the graphene surface, where quenching of the luminescent AgNCs, associated with the two probes occurred. Subjecting the graphene oxide scaffold, on which the AgNCs-modified probes ( 15) and ( 16) were deposited, to the HBV gene ( 18) stimulated the removal of the AgNCs-modified probe ( 15) from the graphene surface, leading to the switch-on luminescence of the released NCs associated with the ( 15)/HBV gene duplex. Similarly, the interaction of the graphene oxide modified with the two types of AgNCs/DNA probes with the HIV gene ( 17) led to the release of the AgNCs-functionalized ( 16)/HIV gene duplex and to the switched-on luminescence of the 775 nm luminescent AgNCs. By treating the graphene oxide sensing platform with the hepatitis B virus (HBV) gene and the HIV gene, the two AgNCs-modified probes adsorbed on the graphene oxide were removed through the formation of the ( 15)/HBV gene and the ( 16)/HIV gene duplexes, leading to the concomitant switched-on luminescence of the 616 and 775 nm AgNCs. The multiplexed analysis of the genes of the two probes adsorbed on graphene oxide is presented in Figure 3d. An analogous aptasensor platform for analyzing ATP and thrombin by the respective aptamers linked to the two different luminescent NCs, in the presence of graphene oxide, was demonstrated. Stimuli-responsive nucleic-acid-gated drug carriers Nanoparticles and microparticles have found growing interest as functional carriers of drugs.93,94 The high volume-to-weight of these nano/microcarriers and eventually, their porous structures provide means to load carriers effectively with drugs. Moreover, the nano/micro dimensions of the carriers facilitate their permeation into cells or biological tissues. Further, the surface modification of the carriers provides versatile strategy for functionalization of the carriers with cell-targeting ligands, in particular, to introduce stimuli-responsive gating units that release the drugs in the presence of triggering biomarkers or auxiliary conditions specific to certain cell environments. The development of such stimuli-responsive nano/micro drug carriers could, thus, provide “smart materials” for nanomedicine by introducing advanced materials for the selective targeted and controlled release of drugs.95,96 Different nano/micro carriers have been developed in the past decade and these include micelles, vesicles, microcapsules, inorganic nanoparticles, such as SiO2 or TiO2, organic polymer nanoparticles, such as biocompatible polymer-based capsules, and highly porous metal–organic-framework (MOFs) nanoparticles.97–99 Different triggers, such as pH,100 light,101–103 temperature,104 redox reagents,105,106 enzymes,107,108 are used to unlock gated drug carriers and to stimulate the release of drugs. The reversible triggered reconfiguration of nucleic acid structures (see Introduction), the synthetic means to conjugate nucleic acids to surfaces, and the possibility to use the information encoded in nucleic acids to tailor complex 2D or 3D structures provide a rich “tool-box” for the integration of nucleic acids with nano/microcarriers into hybrid stimuli-responsive drug carriers. Indeed, substantial progress has been demonstrated with the design of stimuli-responsive nucleic-acid gated nano/microcarriers, such as SiO2 nanoparticles,109 all-DNA microcapsules,95 nucleic-acid-based hydrogel microcapsules,110 and nucleic-acid-functionalized MOF nanoparticles.111 In the forthcoming section, examples of stimuli-responsive nucleic-acid-based nano/micro hybrid carriers would be introduced, and the significance of the nano-/microstructures for developing the area of nanomedicine would be elaborated. Mesoporous SiO2 nanoparticles provide an attractive carrier for drugs. The pore structures of the SiO2 matrix (2.5 nm diameter) provide a means of loading the drugs and capping the pores with stimuli-responsive gating units that enables the unlocking of the pores, and the release of the drugs, in the presence of appropriate triggers. Specifically, the gating of the pores with stimuli-responsive nucleic acids provides a means of releasing the l