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Spherical Nucleic Acids: Turning Synthetic Advances and Fundamental Discovery into Translational Breakthroughs in Chemistry, Materials Development, Biology, and MedicineClick to copy article linkArticle link copied!
- Connor M. ForsythConnor M. ForsythInterdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, Illinois 60208, United StatesInternational Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United StatesMore by Connor M. Forsyth
- Rachel R. ChanRachel R. ChanDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United StatesInternational Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United StatesMore by Rachel R. Chan
- Tanner D. FinkTanner D. FinkDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United StatesInternational Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United StatesMore by Tanner D. Fink
- Janice KangJanice KangDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United StatesInternational Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United StatesMore by Janice Kang
- Jacob D. CohenJacob D. CohenInterdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, Illinois 60208, United StatesInternational Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United StatesMore by Jacob D. Cohen
- Sarah Hurst PetroskoSarah Hurst PetroskoDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United StatesInternational Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United StatesMore by Sarah Hurst Petrosko
- Chad A. Mirkin*Chad A. Mirkin*Email: [email protected]Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, Illinois 60208, United StatesDepartment of Chemistry, Northwestern University, Evanston, Illinois 60208, United StatesInternational Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United StatesMore by Chad A. Mirkin
Abstract
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Conspectus
Early research in nanoscience and nanotechnology focused on gaining synthetic control over the size, shape, and composition of nanostructures, as well as exploring their fundamental properties. Over the past few decades, these capabilities have become increasingly sophisticated. Today, we have well-established synthetic toolkits and methodologies that enable the design of nanostructures with tailored properties and functions, guided by sets of design rules, for use in many areas spanning biology and medicine to energy, the environment, and catalysis.
To illustrate this paradigm, where synthesis and fundamental discovery drive engineering and technological innovation, we examine spherical nucleic acids (SNAs) as a case study. SNAs are nanoconstructs consisting of a nanoparticle core densely functionalized with a radially oriented oligonucleotide shell. Over the past 30 years, the evolution of SNAs has spanned their invention, the development of increasingly advanced syntheses enabling the creation of dozens of SNA classes (and related DNA-functionalized anisotropic materials, often termed programmable atom equivalents [PAEs]), the discovery of novel phenomena that have reshaped core chemical principles, and their translation into nanomedicines, biological labels, and synthons in materials science.
SNAs were first developed in 1996 as gold nanoparticle–DNA conjugates. Since then, extensive study has revealed common structural features that are tied to their unique properties, defining SNAs as a distinct materials class. Most SNAs feature a core (typically a nanoparticle, though recent advances involve molecular scaffolds) that concentrate nucleic acid strands into close proximity. This architecture confers several distinctive properties: enhanced binding affinity to complementary DNA (both free and surface-bound), resistance to enzymatic degradation, reduced immune activation (unless specifically designed for immunostimulation), and efficient cellular uptake without requiring transfection agents.
These synthetic and fundamental advances offer significant advantages in biomedical probe and therapeutic design. Due to their modularity, stability, biocompatibility, and ability to access intracellular compartments, SNAs have been applied as intracellular and extracellular probes, tools for gene regulation, vaccines, and gene editing platforms (especially when coupled with CRISPR/Cas9 technology). In parallel, SNAs serve as foundational elements in a new class of programmable matter: DNA-mediated colloidal crystals. Here, sequence-specific DNA interactions are used to organize SNAs into three-dimensional, periodic structures. This line of inquiry has enabled the design and synthesis of thousands of crystal variations, with different lattice symmetries, parameters, and nanoparticle compositions, unlocking the potential for novel optical and mechanical metamaterials and catalysts with exceptional properties, such as negative refractive indices, shape memory, and second harmonic generation. In sum, SNAs exemplify how synthetic mastery and fundamental discovery can catalyze innovation across disciplines, providing a framework that chemists can use in developing transformative new materials.
This publication is licensed for personal use by The American Chemical Society.
Copyright © 2026 The Authors. Published by American Chemical Society
Key References
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Mirkin, C. A.; Letsinger, R. L.; Mucic, R. C.; Storhoff, J. J. A DNA-based method for rationally assembling nanoparticles into macroscopic materials. Nature 1996, 382, 607–609. (1) This paper introduces spherical nucleic acids (SNAs) and the concept of the nanoparticle “atom” and the DNA “bond”. It discusses SNA synthesis and characterization as well as their use in colloidal crystal engineering with DNA to generate programmable matter.Rosi, N. L. ; Oligonucleotide-Modified Gold Nanoparticles for Intracellular Gene Regulation. Science 2006, 312, 1027–1030. (7) This paper highlights the first demonstration of the ability of SNAs to enter cells in high quantities as single entity agents, an unexpected result at the time. This discovery laid the foundation for SNAs as intracellular probes and therapeutic agents.Macfarlane, R. J. ; Nanoparticle Superlattice Engineering with DNA. Science 2011, 334, 204–208. (10) This paper describes the first design rules for SNA-based colloidal crystals, enabling control over crystallographic parameters (composition, symmetry, and lattice constant). It introduces the complementary contact model (CCM) for designing structures based upon particle arrangements that maximize DNA bonding interactions.Wang, S. ; Rational vaccinology with spherical nucleic acids. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 10473–10481. (6) This paper introduces rational vaccinology, where the structures of SNA immunotherapeutics, not solely the composition (i.e., medicinal components), dictate their potency through control of target engagement and signaling kinetics. It lays the foundation for the broader field of structural nanomedicine.
I. Introduction
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The interplay between scientific discovery and engineering is central to driving technological progress. This relationship is particularly critical in nanoscience and nanotechnology, where advances in synthesis methodology and fundamental structure–property relationships directly enable the preparation of new types of materials and devices with useful capabilities and functionalities. Chemical synthesis can be used to access a near-infinite number of unique nanostructures of various sizes, shapes, and compositions. In the case of multicomponent nanostructures, different structural parameters can be tuned independently. So, the chemist has an almost unlimited capacity to build new materials, explore structure–function relationships, and exploit these structures and knowledge in applications spanning medicine to energy and the environment to catalysis. Overall, synthetic advances and scientific discoveries, especially those that link structure and function, drive engineering outcomes because the structure of a nanomaterial dictates its properties. To illustrate this paradigm, a distinct synthesis–discovery–invention framework is provided using the discovery and evolution of spherical nucleic acids (SNAs) as a defining case study; an in-depth chemical understanding of a novel nanoscale system can lead to a deep appreciation for the key features that can be exploited for its development to address major scientific and technological challenges.
Spherical nucleic acids are nanoconstructs typically characterized by a nanoparticle core with a densely packed and radially oriented nucleic acid shell (Figure 1A). (1−3) The first versions of these nanomaterials were introduced in 1996─the prototypical SNAs were comprised of a gold nanoparticle (∼13 nm diameter) core and a DNA shell. (1) Subsequently, synthetic advances have led to the realization of dozens of different SNA classes with a variety of core and shell types as well as analogous DNA-modified structures with anisotropic cores. Modularity permits chemists to make large libraries of programmable atom equivalents (PAEs) (4,5) (including SNAs) with gradients of structural differences, especially since the features of the core and the shell can be tuned independently; all SNAs share common structural characteristics that give rise to unusual properties that define them as a materials class. In the case of SNAs, structure–function relationships have been extensively explored, especially in the context of structural nanomedicine (6−9) and colloidal crystal engineering with DNA. (10) SNA properties make them useful as highly sensitive, selective, and well-defined diagnostic probes, (11−14) potent single-entity agents for gene regulation, (7,15−18) gene editing, (19,20) and immunotherapy, (6,21−23) as well as building blocks for the assembly of programmable matter useful in catalysis, (24) optics, (25) mechanics, (26) and electronics. (27)
Figure 1
Figure 1. Synthetic advances with SNAs. (A) Schematic shows a gold-core SNA radially functionalized with strands of oligonucleotides. (B) SNAs exhibit a high degree of oligonucleotide and core shape modularity. Functional oligonucleotides typically contain three segments: a functional oligonucleotide sequence, a spacer segment, and an attachment group for nanoparticle surface binding. SNA-like properties can be achieved using anisotropic nanoparticle cores including truncated octahedron, truncated octahedral nanoframes, cubes, and triangular prisms. Adapted with permission from ref (206). Copyright 2022 Springer Nature Ltd. (C) SNA diameter is dependent on the core size and oligonucleotide shell length. Both parameters can be tuned independently. SNAs of the same diameter can be prepared using different core sizes and DNA shell lengths. Adapted with permission from ref (10). Copyright 2011 American Association for the Advancement of Science. (D) To date, SNAs have been synthesized using a variety of core materials that allow access to vastly different physicochemical properties. Core materials have included both inorganic and organic cores, and they endow the SNA structures with specific properties (e.g., plasmonic and enzymatic) based on composition. Pictured are a selection of different SNAs with a diversity of core materials, including molecular, protein, gold, liposomal, and lipid nanoparticle cores ranging in size from ∼1 to >150 nm. The representation of a CRISPR SNA is adapted from PDB ID 8UZA. ePMV software was used in the generation of panels A, B, and D, ref (250).
Therefore, when we are examining the connection between synthetic advances and fundamental discovery as a route to engineering solutions to pressing scientific and technological challenges, SNAs are an interesting case study. Over the past 30 years, SNAs have proven to be an ideal system for delineating structure–function relationships, and for exploiting them in systems that have not only proven useful in laboratory settings, but also in the real world as diagnostic probes and therapeutic agents (including the clinic, i.e., NCT03020017, NCT03086278, and NCT03684785). (18,28,29) In this way, the SNA can be a roadmap for others in the field that are looking for a deliberate approach to materials design, discovery, and application.
II. Synthetic Advances Underpinning Scientific Discovery with SNAs
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Scientific discovery in chemistry often relies on synthetic advances, including with SNAs (Figure 1). The physical and chemical properties of SNAs, like other nanomaterials, are highly dependent on their size, composition, shape, and overall structure. (4,30,31) Therefore, the ability to independently control each of these parameters and understand the implications of such structural changes on properties permits the preparation of designer materials with targeted functionalities. The versatility of the SNA platform to accommodate different nanoparticle cores (e.g., organic and inorganic particles with various sizes and surface chemistries) and oligonucleotide shells (e.g., oligonucleotide with different sequences, lengths, and chemistries) allows it to be formulated for a variety of purposes to an extent not possible with many other types of nanostructures (Figure 1A,B). The synthetic advances described in this section have made a variety of scientific discoveries and engineering outcomes possible.
II.i. Synthetic Advance: Ability to Control SNA Size
The first types of SNAs utilized 13 nm gold nanoparticles as cores and 20–30-mer synthetic DNA strands as shells. (1) These components were utilized in part because the synthesis of each was well-established, and facile coupling chemistry could be used to form molecular layers on gold nanoparticle surfaces (e.g., via alkylthiolated DNA strands). Subsequently, SNAs have been synthesized from gold nanoparticle cores ranging in diameter from ∼1 to 200 nm. (32,33) Uniform gold particles (exhibiting a typical polydispersity index < 0.2, depending on size) can be easily made, are straightforward to characterize, and are relatively stable/inert. (34−36) The oligonucleotides used in SNA synthesis are typically short (15–30 base pairs; lengths that can be achieved using standard solid-phase synthesis techniques), but multiple segments of DNA have been hybridized together to form longer sequences (i.e., > 50 base pairs) to precisely control SNA shell thickness. (10,37) Both the core size and DNA length of SNAs can be tuned independently. Consequently, SNAs with similar hydrodynamic radii can be synthesized from different nanoparticle core sizes by adjusting the DNA length. For individual SNAs, each base pair adds approximately 0.34 nm to the particle’s effective diameter. (38) When SNAs are assembled into ordered lattices in colloidal crystal engineering, an effective rise of ∼0.26 nm per base is used to model interparticle distances. (10) For example, to target a specific interparticle spacing in such a lattice, SNAs with ∼25 nm radii have been made from either smaller (∼5 nm radii, ∼80-base DNA) or larger gold particles (∼10 nm radii, ∼60-base DNA) (10) (Figure 1C).
The SNA core often accounts for the larger portion of SNA hydrodynamic diameter, and the lengths of the attached oligonucleotides are chemically well-defined and uniform because they are made via solid-phase techniques and subsequently purified. Therefore, core size, as opposed to oligonucleotide composition and length, has a larger impact on SNA size and dispersity. Moreover, the ability to control SNA size and polydispersity is not the same for every class of SNA, mainly because different synthetic routes are used to prepare each type of core (Figure 1D). For example, liposomal cores typically have diameters between 30 and 100 nm (polydispersity index ∼ 0.1), (39,40) and molecularly defined cores, such as proteins (proSNAs) typically have diameters between ∼2 and 20 nm, depending on their molecular weight. (19,41,42) A wide range of core sizes and DNA lengths are amenable to SNA synthesis, as long as the DNA strands are able to achieve the sufficient surface densities needed for the conjugate to display the cooperative properties that define these architectures.
The ability to control SNA size is important because it impacts properties like biodistribution and cellular uptake. (32) Therefore, in the field of structural nanomedicine (where the structure of nanoscale drugs, in addition to their composition, dictates their potency), size is an important parameter. (8,9) Furthermore, in colloidal crystal engineering with DNA, certain design rules for preparing colloidal crystals hinge on the absolute or relative sizes of the SNAs in the crystals. (10) For example, with SNAs, the hydrodynamic radii, not the individual sizes of the two cores and the associated DNA shells, dictate particle crystallization. The sizes of SNA building blocks and their surface DNA loading also influence their metallicity, or mobility, in a particle lattice. (43)
II.ii. Synthetic Advance: Ability to Independently Control Composition and Structure of SNA Core and Shell
The core and shell composition of SNAs can be independently tailored, with each component influencing the overall properties of the conjugate structure. For instance, DNA-based SNAs with gold nanoparticle cores exhibit strong optical extinction in the visible spectrum due to localized surface plasmon resonance (LSPR); ∼13 nm gold particles display an LSPR peak centered around 520 nm. (44) In contrast, SNAs with other inorganic cores, such as silver, (45) silica, (46,47) metal oxide, (30,48) and semiconductor nanoparticles, (49,50) possess distinct optical properties. For example, silver nanoparticles possess size-dependent surface plasmon resonances between ∼390 and 420 nm and exhibit higher extinction coefficients at similar sizes relative to gold nanoparticles. (51,52) Beyond inorganic materials, SNAs also have been synthesized using organic and biological cores, including micelles and extracellular vesicles, (53−55) FDA-approved polymers like poly(lactic-co-glycolic acid) (PLGA), (56) liposomes, (39) proteins (proSNAs), (57) and lipid nanoparticles. (58) These cores are nonplasmonic, and their biocompatibility is often more critical than their optical behavior. Finally, hollow (core-less) SNAs have been created through methods such as catalytic cross-linking of oligonucleotides on gold nanoparticles followed by particle dissolution, (59) or by employing hollow liposomes. (39) These hollow structures enable the formation of colloidal crystals with symmetries not found in nature through “design by deletion” strategies, (60) and they also offer space for encapsulating therapeutic cargo for nanomedicine applications. (61)
In the context of SNA shells, synthetic oligonucleotides offer a high degree of programmability. Chemists can precisely design their sequence, length, backbone, and various chemical functionalities. A wide range of DNA sequences and lengths (from 8 to over 100 base pairs) (1,10) have been employed, along with RNA, (62) peptide nucleic acid (PNA), (63,64) and locked nucleic acid (LNA). (65,66) These strands are typically terminated with a chemical functionality that facilitates either covalent attachment (e.g., a thiol group for gold-core SNAs (1)) or noncovalent binding (e.g., sterol or lipid modifications for liposomal SNAs (39,67)). Dibenzocyclooctyne (DBCO)-modified DNA and amphiphilic azide-functionalized polymers enable a generalizable approach to SNA formulation across a variety of inorganic cores. (30) Moreover, functional moieties such as antibodies (68) or peptides (69) can be incorporated into the oligonucleotides for targeted delivery, while fluorescent dyes or quantum dots may be included for detection and tracking. (70−72) Notably, multiple modifications can be introduced onto a single oligonucleotide strand using orthogonal chemistries. (12) The stability of SNAs is significantly influenced by the characteristics of the oligonucleotide shell, including surface density, strand length, and backbone chemistry. (73−75)
The properties of SNAs are heavily influenced by their oligonucleotide shell densities, (76) which dictate surface charge, hydrophobicity, cooperative binding, and other characteristics. In fact, a high enough DNA density is needed to elicit the cooperative binding properties that define SNAs. Early synthetic methods relying on salt-aging established a benchmark for DNA loading density on gold nanoparticle-core SNAs as a function of particle size. (77) Subsequently, freezing or dehydration have been used to further increased the DNA densities achievable on inorganic core SNAs, (78−81) and in parallel, new analytical methods have been developed to accurately and efficiently determine DNA loading on SNAs. (82−84) Studies correlating DNA density with the emergence of hallmark “SNA-like” properties indicate that a threshold of approximately 1.5 pmol/cm2 (calculated at the SNA’s outer surface) is needed. (85) Interestingly, the onset of rapid cellular uptake, a key feature of SNAs, is nonlinear with respect to DNA surface density; a sharp increase in uptake is observed once a threshold DNA density is reached, beyond which further increases in DNA density do not appreciably enhance cellular uptake. (86,87)
The ability to finely tune the parameters of oligonucleotides within SNA shells has enabled the design and development of novel colloidal crystals engineered using DNA. For instance, interparticle spacing can be precisely adjusted, down to the subnanometer scale, by varying the length of the DNA strands. (10,37) More broadly, the tunability of the SNA shell supports a modular or “digital” approach to nanomedicine, where different diseases can be targeted simply by altering the oligonucleotide sequence (88) on an SNA-based probe, therapeutic, (89) or theranostic agent. (90) In gene regulation applications, DNA- and RNA-based SNAs have been utilized in antisense (7) and RNA interference (RNAi) (62) pathways, respectively, allowing for gene-specific targeting based on sequence complementarity. Additionally, SNAs composed of immunostimulatory or immunosuppressive nucleic acid sequences have been tailored to elicit specific immune responses. (91)
II.iii. Synthetic Advance: Ability to Control Shape (i.e., Prepare Anisotropic Analogues to SNAs)
The term “programmable atom equivalent”, or PAE, was coined to encompass both SNAs and their anisotropic equivalents, structures that consist of an anisotropic nanoparticle “atom” core and that interact via DNA “bonds”. (4,5) The spherical nanoparticles that form the core of SNAs act as scaffolds for the isotropic, radial presentation of the oligonucleotides densely packed on their surfaces. The use of anisotropic nanoparticles as scaffolds for DNA functionalization has permitted oligonucleotide presentation that retains the shape of the anisotropic particle (if within the “zone of anisotropy”). (92) The “zone of anisotropy” refers to the phase space of anisotropic PAE bonding, where the length of the DNA ligands relative to the nanoparticle size preserves the anisotropy of the core geometry. The ability to prepare anisotropic PAEs has led to the realization of directional bonding interactions in DNA-mediated nanoparticle assembly that has been used to prepare new classes of colloidal crystals, including those based on shape complementarity that favor the formation of highly ordered space-filling structures (geometries that favor space tessellation). (93−95)
The preparation of anisotropic SNA analogues was fueled by advances in noble metal nanoparticle synthesis and purification. Thermal, (96) photochemical, (97) and seed-mediated syntheses (98,99) and improved purification processes, involving centrifugation, (100) depletion flocculation, (101,102) or selective overgrowth and precipitation steps, (103) for anisotropic noble metal particles have been developed. Moreover, methods have been devised to densely functionalize anisotropic nanoparticles with DNA on particular facets while retaining particle shape. (104,105) Anisotropic PAEs consisting of a variety of sizes and compositions (mainly noble metals) have been prepared using nanorod, triangular prism, cube, octahedron, bipyramid, concave cube, and more recently, hollow nanoframe and nanocage cores. (106) Proteins, (107) “patchy particles”, (108,109) and DNA origami constructs (110) have also been used to confer directionality (or valence) to bonding interactions between colloidal building blocks by leveraging nonuniform surface chemistries, rather than only core shape. Taken together, the ability to precisely control the physical and chemical properties of SNAs and their anisotropic equivalents though the fine-tuning of their sizes, structures, and compositions makes them an extremely powerful platform in materials science and nanomedicine.
III. From Scientific Discovery to Engineering Outcomes with SNAs
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The interplay between scientific discovery and engineering outcomes is important in any field of science because this synergistic connection drives translation. In the following 10 examples, we utilize SNAs as a case study to demonstrate the importance of leveraging scientific discoveries to drive engineering outcomes and ultimately technological innovation.
III.i. Scientific Discovery: Spherical Nucleic Acids Exhibiting Distance-Dependent Optical Properties. Engineering Outcome: Colorimetric Detection
In the late 1990s, it was demonstrated that introducing a DNA linker strand, partially complementary to DNA strands on the surfaces of two different types of gold nanoparticle-core SNAs, into solution induced hybridization events that led to the formation of large nanoparticle assemblies (Figure 2). (1) This assembly process could be monitored using the naked eye (Figure 2A), UV–visible spectroscopy, or simple spot tests (Figure 2C, left). The striking color change is attributed to the optical properties of the gold nanoparticle cores and is reversible with temperature. (1)
Figure 2
Figure 2. Fundamental research and engineering development with SNA-based probes. (A) Solutions of gold nanoparticle-core SNAs before (left; dispersed particles are red) and after the addition of a target DNA sequence links the SNAs (right; aggregated particles are purple). (B) Melting curves show free DNA and the same DNA attached to a gold-core SNA and a core-free polyvalent nucleic acid nanostructure (PNAN) (left); enthalpies and entropies of DNA hybridization to linear DNA and SNAs are derived from a concentration-dependent fluorescence hybridization assay (right). Panel B, left: Adapted with permission from ref (59). Copyright 2011 American Chemical Society. Panel B, right: Reprinted with permission from ref (131). Copyright 2018 American Chemical Society. (C) Example shows polynucleotide target detection using the colorimetric Northwestern Spot Test (left). Solutions of SNA probes were mixed with a fully complementary target strand (Target), without the target (No Target) and with a target contaning a single base pair mismatch (Mismatch Target) and heated to the indicated temperature. Note the high degree of discrimination between the fully complementary and mismatched targets, allowing for the detection of single nucleotide mismatches. Example shows the first SNA-based scanometric detection system wherein oligonucleotide arrays were treated with target strands (either fully complementary [A] or with a single base pair mismatch, substituting A for G, T, or C) and SNA probes were developed at the indicated temperatures (right). Panel C, left: Adapted with permission from ref (112). Copyright 1997 American Association for the Advancement of Science. Panel C, right: Reprinted with permission from ref (126). Copyright 2000 American Association for the Advancement of Science. (D) Chip-based multiplexed scanometric detection of barcode-DNA strands are released from SNA probes after incubation with DNA targets derived from the human immunodeficiency virus (HIV), Ebola virus (EV), variola virus (VV), and hepatitis B virus (HBV), or a mixture of all four (Mix). Adapted with permission from ref (139). Copyright 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. ePMV software was used in the generation of panel A, ref (250).
In solution, when the distance between particles exceeds their diameter, a narrow localized surface plasmon resonance (111) (LSPR) peak appears centered around 520 nm (for 13 nm gold nanoparticles), (44) and the solution appears red. (112) However, when hybridization via the complementary DNA linker brings SNAs into close proximity (such that the interparticle distance is less than the particle diameter) plasmonic coupling occurs. This action shifts the LSPR to longer wavelengths (centered around 580 nm for 13 nm particles). This coupling dampens the magnitude of the LSPR peak and shifts its maximum, causing the solution color to shift from red to purple or blue (Figure 2A). The length of the DNA linkers influences the extent of the LSPR red-shift by modulating both the SNA aggregate size and interparticle distance. (113)
Rapid and highly specific colorimetric detection systems were developed based on this fundamental scientific discovery, (114) first for nucleic acids, but then for a variety of other moieties, such as metal ions, (115−117) intercalators, (118) proteins and enzymes, (119−123) and small molecules (124) in single and multiplexed formats. These colorimetric methods are simple, easy to perform, require only low-cost instrumentation, and are often highly sensitive (for example, single-base pair mismatches can be detected). (125) In the simplest iteration, target oligonucleotides induce particle aggregation when mixed with two complementary SNA probes, enabling spectrophotometric detection (Figure 2C, left). Later, higher-sensitivity approaches were developed, including the scanometric assay (Figure 2C, right), where target strands are sandwiched between probe sequences immobilized on a DNA chip and incoming probe SNAs. (126) After target capture, the light scattering of the nanoparticles are enhanced via silver deposition for readout (Figure 2D). These innovations allowed for the detection of nucleic acids and protein targets with between 1 and 6 orders of magnitude greater sensitivity than contemporary fluorescence-based assays, (119,126,127) and were later commercialized as the Verigene system (initially via Nanosphere and now by Luminex/DiaSorin). (128) Ultimately, this example highlights how a fundamental discovery focused initially on materials design can lead to the development of impactful diagnostic technologies.
III.ii. Scientific Discovery: Nucleic Acids on Particle Surfaces Exhibiting Cooperative, Higher Affinity Target Binding Properties. Engineering Outcome: High-Sensitivity and High-Selectivity Detection
SNAs have unique, structure-dependent properties that distinguish them from free DNA of the same sequence. They exhibit higher melting temperatures (Tms) and exceptionally narrow melting transitions (based on the full width at half-maximum (FWHM)) (Figure 2B, left). In one system, the FWHM of the melting transition of SNAs was 2 °C compared to 13 °C for the analogous free DNA, and the Tm was 15 °C higher (DNA Tm = 51 °C vs SNA Tm = 66 °C). (129) Furthermore, quantitative thermodynamic investigations revealed that SNA probes can hybridize to free complementary sequences with binding constants that are approximately 2 orders of magnitude higher than with the free DNA strand. (130) Importantly, the increase in binding affinity was found to be a result of the dense surface coverage of DNA on the nanoparticle core─a defining feature of SNAs.
To understand and model SNA-specific properties, researchers investigated the thermodynamic origins of SNA binding. DNA hybridization on SNAs is more energetically favorable than with nonparticle-bound DNA, reflected by more negative associated Gibbs free energy changes. (131) Interestingly, while SNAs benefit from favorable binding enthalpy due to surface-based structural confinement that positions DNA in energetically favorable conformations, they incur a higher entropic penalty (Figure 2B, right).
In addition, the binding constants between SNAs with varied fractions of prehybridized strands and free oligonucleotides were studied to understand the impact of nanoscale confinement and steric and electrostatic crowding on DNA hybridization. As the proportion of duplexed DNA increases on SNAs, subsequent binding events become increasingly less enthalpically favorable due to the electrostatic repulsion between neighboring strands. As a result, the binding constant of complementary DNA decreases by approximately 3 orders of magnitude when the percentage of prehybridized DNA on the SNA surface increases from 0 to ∼30%. (132) Surprisingly, structurally imposed conformations of DNA strands at high proportions of duplexed DNA result in entropic stabilization for subsequent binding events in a mechanism analogous to allostery. These studies show how thermodynamic factors that arise from electrostatic repulsion, DNA hybridization, and entropic contributions fundamentally alter the properties of SNAs compared to linear DNA.
In turn, these lessons enabled researchers to rationally tune structural parameters, such as DNA sequence, surface density, and linker length, to deploy them as selective biosensors with a high degree of stringency in detecting dilute target sequences. (132,133) For instance, a scanometric DNA chip array assay was developed that can discriminate single-nucleotide mismatches with extraordinarily high selectivity. (126) Additionally, the “bio-barcode (BBC)” assay, (134−137) which employs an SNA probe-based amplification method, has proven effective in both single- and multiplex formats (138−140) for detecting oligonucleotides and proteins, including prostate-specific antigen at concentrations as low as 3 aM. (119,141) More complex systems have leveraged SNAs bearing functional DNA sequences. For example, DNAzymes formulated as SNAs (termed SNAzymes) have been used to create sensors with excellent sensitivities, selectivity, and stabilities, including for the detection of uranyl ions in both solution (142) and living cells, (143) enzymes, (144) and microRNA via colorimetric (145) or (electro)chemiluminescent (146−150) readouts (limits of detection in the atto-femtomolar range). (151) The detailed understanding of SNA cooperativity has been fundamental to enabling these ultrasensitive and highly selective diagnostic tools.
III.iii. Scientific Discovery: Gold Core of SNA Gold Nanoparticle Conjugates Catalyzes Cross-Linking of Alkyne-Based Adsorbates. Engineering Outcome: Preparation of Hollow SNAs and All-Nucleic Acid Nanomaterials
The gold cores of SNA gold nanoparticle conjugates can catalyze chemical reactions that cross-link alkyne-based adsorbates, enabling the synthesis of core-free, all organic SNAs. (59,152) In this case, the gold nanoparticle core functions both as a template and as a catalyst for the cross-linking of polymers bearing pendant propargyl ether groups, taking advantage of the alkynophilicity of Au(0) surfaces. (152) Upon removal of the gold nanoparticle via oxidative etching, stable and well-defined hollow SNAs were formed. The size of the gold nanoparticle could be adjusted to control the size of the resulting SNA. Using this concept, the design space of SNAs was expanded. (59) This new class of SNA, termed polyvalent nucleic acid nanostructures (PNANs), exhibits many of the same properties as the cored versions, including narrow melting transitions and resistance to nuclease degradation, offering compelling evidence that many SNA properties are core-independent, which has inspired researchers to explore other unconventional-at-the-time types of SNA core materials.
In colloidal crystal engineering with DNA, hollow SNAs were used as three-dimensional spacers within programmable nanoparticle superlattices to realize new symmetries, including an unprecedented “lattice X” configuration. (60) In this case, the fundamental discovery that gold nanoparticles could catalyze particular chemical reactions at their surface led to a synthetic advance in our ability to prepare a new class of SNA that enabled the synthesis of an engineered lattice symmetry never before observed in nature. In nanomedicine, these SNAs opened up the possibility of the design and development of other structures that were composed entirely of organic components and that would alleviate potential concerns about the use of gold nanoparticles in SNA therapeutics. (91,153)
III.iv. Scientific Discovery: SNA Resistance to Nuclease Degradation and no Significant Immune Response (Unless Designed to do so Based on Sequence). Engineering Outcome: Stability in in Vivo and in Vitro Biological Environments and High Compatibility with Cells and Tissues
SNAs exhibit remarkable resistance to nuclease degradation and are relatively nonimmunogenic, owing largely to their 3D architecture (Figure 3). Compared to free linear DNA, SNAs exhibit significantly greater stability in the presence of nucleases (Figure 3A). Specifically, SNAs have a 4.3-fold longer half-life (100 ± 16 min) when incubated with DNase I, compared to linear DNA (half-life of 23 ± 4 min). (74) This increased stability arises from slower enzymatic hydrolysis of SNAs. The dense, negatively charged DNA shell of SNAs attracts counterions to the nanoparticle surface, which can inhibit nuclease activity. (75) Higher oligonucleotide loading densities and greater associated charge contribute further to this enhanced stability. These findings highlight the importance of using robust chemical linkages to attach DNA strands to the nanoparticle surface. Any reduction in surface DNA density, such as through strand dissociation, can compromise the structural integrity of SNAs and increase their susceptibility to enzymatic degradation.
Figure 3
Figure 3. Scientific discoveries and engineering outcomes of SNAs in nanomedicine research. (A) The dense 3D DNA shell of SNAs confers enhanced resistance to nuclease degradation relative to linear oligonucleotides. This protection arises from slower enzymatic hydrolysis, as the negatively charged and sterically bulky shell inhibits nuclease activity. The protein corona that forms on SNAs in biological media is not depicted. FAN1 Nuclease PDB ID 8S5A. (B) Compared to linear or transfected oligonucleotides, SNAs exhibit high cellular uptake due to their multivalent interactions with class A scavenger receptors, which facilitate endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. The representation of scavenger receptors is adapted from PDB IDs 2QIH and 7DPX. (C) Their high uptake efficiency, stability, and limited activation of host immune responses enable SNAs to function broadly as tools in both in vitro and in vivo systems. This versatility supports their use in intracellular detection, imaging, gene regulation, and immunotherapy. (D) Detection probes, including nanoflares, sticky-flares, and FIT-flares, have been engineered to sense intracellular RNA, ions, small molecules, and diseased tissue in vivo, as well as to perform live-cell genetic and metabolic analysis. These probes incorporate fluorophores that are either released or activated upon target binding, generating sensitive and responsive readouts. (E) As gene regulation agents, SNAs can be constructed from DNA or RNA to modulate expression through antisense or RNA interference pathways. As immunotherapies, they stimulate both innate and adaptive immune responses and have shown promise as nanomedicines for treating diverse cancers and infectious disease. The representation of a CRISPR SNA is adapted from PDB ID 8UZA. ePMV software was used in the generation of panels A, B, D, and E, ref (250).
In addition to enhanced oligonucleotide stability, the SNA architecture also significantly reduces the intrinsic immunogenicity of their oligonucleotide components at both the cellular and organismal levels. Early work demonstrated that gold-core SNAs with covalently modified oligonucleotides exhibit limited immunogenicity and cytotoxicity in vitro, despite their high cellular uptake. (154−156) Subsequent investigations have explored the magnitude of innate immune responses elicited by SNAs in vivo to determine whether the architecture can mitigate cytokine release syndrome, characterized by rapid cytokine release and severe systemic inflammation. (157,158) Liposomal SNAs prepared using immunostimulatory DNA (CpG DNA) were found to induce lower acute levels of proinflammatory cytokines IL-6, TNF-α, IFN-γ, IL-12p70, and MCP-1, which contribute to excessive inflammation and tissue damage, compared to linear CpG DNA. (67,159) Importantly, SNA use also resulted in lower levels of anti-inflammatory cytokines, including IL-4 and IL-10, which can lead to a dampening of a desirable immune response. These results suggest that an adverse immune response can be triggered by DNA inadvertently released from an SNA, implicating construct stability as a critical design parameter. (160) Accordingly, the stability of liposomal SNAs can been enhanced via the choice of the anchoring groups (67,159,161) and the molecular identity of lipids comprising the liposomes. (162) In sum, the fact that SNAs do not cause excessive, unintended immune activation that can lead to severe and possibly lethal systematic inflammation is vital to their performance as intracellular probes and therapeutics. Indeed, this controlled immune response occurs despite the superior potency of SNAs (relative to linear nucleic acids) to activate pattern recognition receptors (PRRs), including toll-like receptors (TLRs). (91,163) Like some nanoparticle platforms, (164,165) SNAs preferentially distribute to lymphoid organs (58,159) where complex tissue architectures effectively coordinate and sequester cytokine production to prevent excessive systemic release. (166)
III.v. Scientific Discovery: SNAs Exhibiting Cellular Entry in High Quantities Without the Need for Transfection Agents. Engineering Outcomes: Intracellular Detection/Imaging and Therapeutics
SNAs composed of a gold core and a DNA shell were first observed to be efficiently internalized by mammalian cells in 2006. (7) These SNAs rapidly entered a variety of cell types (including RAW 264.7, HeLa, NIH-3T3, and MDCK cells) with >99% uptake efficiency, without inducing detectable changes in cellular morphology. Since this discovery, SNAs have been shown to enter over 60 different cell types as single entities, without the need for transfection agents, which are often cytotoxic. (159,167) Subsequent studies have shown that other types of SNAs, such as those with RNA shells or alternative core compositions, are also readily taken up by cells. Cellular uptake depends on several factors, including SNA size, oligonucleotide sequence, and surface density. For example, SNAs bearing guanine (G)-rich sequences and those with higher DNA surface densities typically (but not always) exhibit enhanced uptake. (76,86,168)
The primary pathway of SNA internalization is believed to involve multivalent interactions with class A scavenger receptors (SR-A), facilitating endocytosis through a lipid raft-dependent, caveolae-mediated pathway (Figure 3B). (70) The 3D arrangement of oligonucleotides on the nanoparticle surface is thought to contribute to the high binding affinity for SR-A. This model explains the previously observed enhanced cellular uptake: both linear and SNA-form nucleic acids enriched in G are naturally recognized by SR-A, (169) and high DNA-density SNAs promote stronger multivalent receptor interactions. (70) While this pathway is currently considered the primary route of SNA uptake, it is important to note that SNAs of different sizes and compositions may engage alternative pathways to varying degrees. Further investigation is needed to fully elucidate these processes.
Following uptake, SNAs are trafficked through an endocytic pathway, primarily into late endosomes, where they are detected after 24 h. (71) Some SNAs escape the endosomes to the cytosol, where they can regulate gene expression or even engage in gene editing in the nucleus. (19) However, it should be noted that less stable SNA constructs, such as liposomal SNAs, are broken down into their constituents intracellularly and differentially exported over time. (170) Importantly, such mechanistic understanding has enabled the development of new forms of SNAs that more readily escape the endosome via the proton sponge effect (an influx of counterions and water within endosomes that causes osmotic swelling and rupture). (11) These SNAs exhibit higher gene silencing activity (up to 20-fold enhancement) even compared to other forms of SNAs. CRISPR-SNA constructs functionalized with endosome-disrupting peptides (i.e., GALA peptide) and a nuclear localization signal (NLS) appended to a Cas9 protein, enter the cell nucleus and have led to increased gene editing efficiencies (2.4-fold increase in indel frequency of Raw 264.7 macrophages) compared to unstructured mixtures of identical Cas9 protein and single-guide RNA administered using Lipofectamine CRISPRMAX. (19)
The discovery of SNA cellular entry has broadened their applicability as detection and therapeutic agents within biological environments (Figure 3C) and additionally led to their development as intracellular probes and as agents for gene regulation and immunotherapy (Figure 3D, 3E). SNA probes termed nanoflares provide a transfection agent-free method for the quantification of intracellular RNA content in living cells, (13,171−173) and they were commercialized under the trade name SmartFlares (AuraSense and Merck/Millipore) with over 1600 versions developed as tools in the life sciences. Nanoflares are gold-core SNAs hybridized to fluorescent reporter strands. Upon nanoflare binding to intracellular targets, the reporter strands are displaced resulting in a fluorescence turn-on due to separation of the fluorophore-labeled reporter strand from the gold nanoparticle quencher. In addition to genetic content, nanoflares have been designed and formulated to detect ions (143,174) small molecules, (175,176) and diseased tissue in vivo (177−179) and perform live-cell genetic and metabolic analysis. (13,175,180) Sticky flares are a type of nanoflare designed for spatial and temporal intracellular RNA detection. (14,181,182) In addition, advances in the nanoflare platform have enabled the development of probes with enhanced sensitivity and specificity, stronger signal output, reduced false-positive readouts, and multiplexed target detection. (172,181,183−189) SNA-based probes that do not rely on the quenching effects of gold nanoparticles have been prepared, such as those that incorporate duplex-sensitive dyes, (11,12,190) like forced intercalation (FIT) dyes. These new flare designs minimize false-positives because they only exhibit fluorescence turn-on upon binding to a target analyte, rather than unintended DNA degradation, dehybridization, or unwanted interactions with thiols present on biological molecules. (191) Importantly, the use of duplex-sensitive dyes allow biocompatible SNA cores, including proteins and polymer-based nanoparticles, to be utilized, offering new possibilities in intracellular detection. (11,185,192)
The finding that SNAs enter cells also enabled their use as intracellular gene regulation and immunotherapy agents. SNAs formulated with DNA and RNA have been shown to regulate gene expression via antisense (7,193) and RNAi (62) pathways, respectively. SNA agents result in more persistent gene knockdown than linear nucleic acids delivered via traditional transfection agents. Also, SNA immunotherapies have enabled innate and adaptive immune stimulation. (6,91,194) SNAs, which have been lead constructs for seven human clinical trials, have been shown to be powerful nanomedicines for the treatment of brain, (18,195) skin, (196,197) and other cancers via gene regulation and immunotherapy. Moreover, SNA architectures for gene editing allow for high cellular uptake, low immunogenicity, and high loading of functional CRISPR/Cas9 machinery compared to other technologies. (19) By formulating materials that are typically difficult to transfect (such as the assembled CRISPR machinery itself or a plasmid encoding its constituent parts) into an SNA architecture, these materials gain the enhanced biological access characteristic of SNAs, resulting in enhanced biocompatibility, uptake, and editing efficiency. (20) Importantly, SNAs are not simply delivery vehicles; rather, they represent a structural reconfiguration of chemical and biological components. Through the SNA framework, these conjugated materials acquire privileged access to cellular compartments and tissues that would otherwise be less accessible.
III.vi. Scientific Discovery: SNAs Binding with TLRs More Strongly Than Linear Strands and Stimulating the Immune System. Engineering Outcome: Immunotherapeutic Development, Based on Structure in Addition to Composition (Structural Immunotherapy, Specifically “Rational Vaccinology”, a Subfield of Structural Nanomedicine)
SNAs composed of immunostimulatory CpG DNA strongly engage TLR9, localized in the endosomes, via multivalent interactions (Figure 4A). They can increase the activation of TLR9 up to 80-fold compared to their linear counterparts. (91) In fact, the organization of CpG DNA into a SNA architecture increased RAW-blue macrophage activation up to 94-fold compared to linear CpG oligonucleotides. The robust activation of immune cells led to the secretion of pro-inflammatory cytokines, such as IFN-γ and IL-12, and the elicitation of antigen-specific responses, pointing to the potential use of these SNAs as immunotherapeutic agents. (91) Later, these adjuvant-only CpG SNAs were formulated with peptide antigens with different arrangements and connectivity to explore their ability to elicit an adaptive immune response: antigens were either encapsulated in the liposome core (SNA-E), conjugated to oligonucleotides that are hybridized to surface CpG DNA (SNA-H), or anchored directly to the surface (SNA-A) (Figure 4B). (6) Of these three different structures with the same composition (and a simple admixture), SNA-H treatment was the most potent, resulting in minimal tumor growth and 100% survival of HPV-associated tumor (TC-1)-bearing mice through 60 days.
Figure 4
Figure 4. Fundamental research and engineering development with SNA-based immunotherapeutics. Key scientific discoveries such as (A) the multivalent display of CpG DNA on SNAs potently stimulating TLR9 have pioneered the new field of structural immunotherapy. The representation of TLR9 is adapted from PDB IDs 5Y3M and 6US8. (B) Compositionally identical yet structurally distinct SNAs suppress tumor growth differentially, demonstrating the importance of nanoarchitecture in next-generation therapeutic development. Adapted with permission from ref (6). Copyright 2019 National Academy of Sciences. (C) These structure–function relationships extend to more complex therapeutics. The differential placements of MHC-I- and MHC-II-restricted antigens in DA-SNA 1 and 2 substantially alter tumor suppression. Adapted with permission from ref (22). Copyright 2023 Springer Nature Ltd. (D) The oligonucleotide shell of SNAs dictates their circulation and biodistribution, leading to the discovery of new agents that cross the blood–brain barrier (BBB). (E) Gold SNAs bearing Bcl2L12 siRNA labeled with Gd(III) localize in glioma tumor tissue following intracranial injection as shown in magnetic resonance (MR) images (top), hematoxylin and eosin-stained brain sections (middle), and the 3D reconstruction of MR data (bottom). Reprinted with permission from ref (195). Copyright 2013 American Association for the Advancement of Science (AAAS). (F) β-galactosidase-based ProSNA functionalized with transferrin aptamer (upper left) successfully accumulates within the brain (lower left), quantified by radiant efficiency (right). Reprinted with permission from ref (41). Copyright 2022 American Chemical Society. ePMV software was used in the generation of panels A, B, and C, ref (250).
These results led to the establishment of the concept of “rational vaccinology”, where the three-dimensional arrangement of SNA vaccine components, not just their identity, dictates immunological outcomes. (6,198) This framework operates within the broader paradigm of structural immunotherapy, which applies deliberate nanoscale design to modulate immune responses. Ultimately, both concepts are grounded in structural nanomedicine, an overarching principle in nanomaterial design where structure itself serves as a critical, programmable parameter that dictates therapeutic activity, safety, and function across diverse applications in biology and medicine. (8,9)
Subsequent investigations have therefore focused on elucidating key structure–function relationships in the design of SNA vaccines and other related nanomedicines. For instance, the chemical linkages between antigens and oligonucleotides (to impart stimuli-responsive and specific intracellular antigen release) (199,200) and those between CpG DNA and the SNA core were investigated to maximize therapeutic performance. (67,161) Chemical linkers have also been designed such that peptide antigens will be released at different rates upon encountering the reducing environment inside cells to achieve more rapid release and enhanced immune stimulation. (200) In addition, several dodecane oligomers of different lengths, [(C12)n, n = 4–10], were explored as DNA-to-SNA anchors, showing that the most stable anchor, (C12)9, led to the most heightened antitumor responses. (67)
Multiadjuvant (163) and multiantigen (22) SNAs have been developed and shown to stimulate immune responses through multiple biological pathways. Notably, compositionally similar SNA vaccines (differing only in the spatial arrangement of CD4 and CD8 antigens, either encapsulated within the liposomal core or displayed on the particle surface in the “SNA-H” architecture) exhibited striking differences in efficacy (Figure 4C). (22) The most potent antitumor responses were observed when the CD8 antigen was presented on the particle surface and the CD4 antigen was encapsulated (DA-SNA 2). This configuration favorably altered intracellular processing, leading to enhanced priming of both CD4+ and CD8+ T cells.
The near-limitless chemical modularity of SNAs, as demonstrated by these multiadjuvant and multiantigen formulations, highlights the need for high-throughput strategies to identify optimal structural designs. Toward this goal, 800 structurally distinct SNAs were synthesized using combinations of 11 design parameters (including lipid composition, antigen density, and DNA anchoring chemistry) and screened for their ability to stimulate TLR9. (40) Machine learning analyses revealed nonlinear relationships between structural parameters and biological activity. Certain features had a stronger influence on TLR9 activation, and key parameters were found to be interdependent. For example, DNA anchoring strategies (e.g., cholesterol vs diacyl lipid) and backbone chemistries (phosphorothioate vs phosphate) were consistently associated with SNAs that elicited stronger immune responses.
With rational vaccinology, known antigens and adjuvants can be reformulated into curative therapies, as demonstrated in a model of HPV-associated cancer, (6) or into therapies with significantly enhanced efficacy in other cancer models. (21,23,201) The broad efficacy of SNA immunotherapeutics, validated across nine different models of cancer and one infectious disease model to date, (33) results from the synchronized delivery of antigen and adjuvant to the appropriate subcellular compartments of antigen-presenting cells (APCs).
III.vii. Scientific Discovery: SNA Biodistribution and Circulation Time Controlled via SNA Structure and SNAs Crossing the Blood–Brain and Blood–Tumor Barriers. Engineering Outcome: Organ Targeting with SNA Therapies
SNA structures can be engineered to control SNA circulation time and biodistribution in cells and tissues (Figure 4D). For example, the addition of polyethylene glycol (PEG) molecules, which do not interact with SR-A, to the surface of RNA-modified SNAs improve blood circulation half-life by decreasing cellular uptake. (202) In addition, SNAs bearing G-rich sequences, which form G quadruplex secondary structures, formed protein coronae that were richer in serum complement proteins, which are important in immune system function, than the analogous structures bearing poly thymine (T) sequences. (88) Because of this enrichment the G-rich SNAs were taken up in increased numbers, as compared to the poly-T SNAs, by macrophages bearing complement receptors, leading to their increased accumulation in the liver and spleen in vivo. Liposomal SNAs functionalized using cholesterol-modified DNA accumulated significantly in the lungs whereas those functionalized using a diacyl lipid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) accumulated in the kidneys. (159)
Another class of SNA, comprised of a gold nanoparticle and a densely packed siRNA of a sequence that targets the oncogene Bcl2Like12 (Bcl2L12), was shown to cross both the blood–brain barrier (BBB) and blood–tumor barrier to accumulate in tumors of glioma-bearing mice in vivo when administered (Figure 4E). (195) This SNA decreased intracerebral Bcl2L12 expression and enhanced intratumoral apoptosis, which collectively reduced tumor burden. This construct was evaluated in phase 0 human clinical trial with patients with recurrent glioblastoma multiforme (GBM), and SNAs successfully accumulated in the tumors. (18) To achieve brain targeting, β-galactosidase proSNAs have also been conjugated with transferrin aptamers, DNA sequences that fold into 3D structures that bind to widely expressed receptors on the endothelium of the BBB. (41) When the transferrin aptamer-modified proSNAs were administered intravenously, they entered the brain to a much greater extent than β-galactosidase or β-galactosidase proSNAs with a scrambled DNA sequence in mice (Figure 4F). Indeed, proSNA formulations significantly improve intracellular delivery of protein compared to the bare proteins in general. These findings are being exploited to tailor SNA therapeutics in translational development for neurological disorders, including GBM. (18)
III.viii. Scientific Discovery: DNA Programmability and Annealing Processes Used to Drive the Formation of Colloidal Crystals and Tune Lattice Parameters (with Nanometer-Scale Precision), Symmetries, and Crystal Habits in Solution and on Surfaces. Engineering Outcomes: Variety of Interesting Optical, Mechanical, and Catalytic Colloidal Crystals
Through the design rules of colloidal crystal engineering with DNA, (3) base-pairing interactions between single-stranded oligonucleotides (referred to as sticky-ends) can be used to direct the assembly of nanoparticles into colloidal crystals with desired lattice parameters, symmetries, and crystal habits (Figure 5). (203,204) The synthesis of such highly ordered crystals relies on the cooperative nature of many relatively weak DNA sticky-end interactions between PAEs, where the interaction strength can be adjusted by changing the number of bases or the sequence (e.g., GC content). (203) Earlier systems that employed complementary binding regions with greater interaction strength did not readily permit the PAE rearrangement necessary to form the more thermodynamically favored crystal structures; instead, kinetically trapped amorphous aggregates were the result. Cooperative binding, based on the unique three-dimensional architecture of the SNA structure, is critical to engineering outcomes both in colloidal crystallization with DNA and biosensing (vide supra).
Figure 5
Figure 5. Scientific discoveries, materials design, and engineering outcomes through the crystallization of SNAs and other types of programmable atom equivalents (PAEs). (A) The colloidal crystal design space arises from the synthetic advances in SNA preparation, where enthalpy-dominated DNA interactions direct crystallization. Metal nanoparticle core (shape and size) and DNA design determine the lattice symmetry and crystal habit. Scale bars = 125, 75, and 1000 nm from left to right. (B) Enthalpic DNA bonding interactions are maximized with facet registry between anisotropic nanoparticle cores, such as cubes. Scale bar = 500 nm. (C) DNA bonding is maximized along the edges of nanoframes, forming a crystalline symmetry from a non-space-filling polyhedral. Scale bar = 1 μm. Reprinted with permission from ref (206). Copyright 2022 Springer Nature Ltd. (D) Thin films and Winterbottom constructions can be formed from heterogeneous crystal growth on substrates. Reprinted with permission from ref (226). Copyright 2017 American Chemical Society. (E) The refractive index of colloidal crystals can be designed as a function of NP shape, NP size, volume fraction, and symmetry. Reprinted with permission from ref (206). Copyright 2022 Springer Nature Ltd. (F) Colloidal crystals components can be stabilized and used as heterogeneous catalysts. (G) Deterministic placement is shown for single PAEs to couple photonic response (determined by spacing, P) and plasmonic response (distance between Au cube and Au substrate). Reprinted with permission from ref (243). Copyright 2015 American Chemical Society. (H) Colloidal crystals exhibit shape memory upon dehydration and rehydration. The mechanical response of the colloidal crystal due to a reversible change in refractive index results in tunable optical response. ePMV software was used in the generation of panel A, ref (250).
Thermal annealing processes permit SNA-based PAEs to arrange themselves into positions that maximize the extent of DNA hybridization between them to form thermodynamic products. This design rule, referred to as the complementary contact model (CCM), is foundational to understanding crystal growth in the field of colloidal crystal engineering with DNA (Figure 5A). (10) The CCM and other design rules have led to the experimental realization of over 1000 structures spanning many different symmetries to date, including ones traditionally seen with ionic materials like face-centered-cubic (fcc), body-centered-cubic (bcc), and simple hexagonal (sh) structures. (105,204−212) In some cases, exotic structures such as clathrates, (213) quasicrystals, (214) diamond lattices, (215) or other symmetries with no mineral equivalent were prepared. (60,205) Systems have also been designed where DNA structure can be used to induce changes in interparticle spacing or drive PAE lattices toward particular symmetries; these systems have involved, for instance, the use of auxiliary DNA design (216−218) or other molecules, (219) pH, (220) and solvent. (221) Researchers also were able to attain single-crystalline colloid lattices through slow-cooling processes (cooling at 0.1 °C/min as opposed to annealing at the melting temperature) or careful control over nucleation and growth processes. (222,223) The resulting crystal habits often form Wulff polyhedra, the thermodynamically predicted shapes with exposed facets having the lowest surface energies. (224) For example, PAEs programmed to assemble into bcc lattice symmetries using DNA yielded single-crystalline rhombic dodecahedral colloidal crystals upon slow-cooling.
While such early discoveries were established with solution-based, homogeneous crystallization processes, epitaxial, surface-bound colloidal crystal growth with SNAs on surfaces was later explored. (225,226) Using a DNA-modified substrate, colloidal crystals were grown with preferential orientations normal to the surface of the substrate by tuning DNA surface identity (Figure 5D). (227,228) This led to control over large-area thin films, crystal positioning and patterning, and defect engineering through the integration of colloidal crystal engineering with DNA and lithographically defined features on substrates. (229,230) Thus, DNA-mediated nanoparticle assembly is a scalable, bottom-up fabrication method to create on-chip devices, a promising alternative to top-down lithographic techniques. (27)
Using design principles that govern colloidal crystal engineering with DNA, both in solution and on substrates, researchers are now deliberately synthesizing colloidal architectures with tailored functionalities. This design space is significantly broader than in conventional atomic systems because, in colloidal crystal engineering with DNA, the identity of the particle ″atom″ and the nucleic acid bonding characteristics are decoupled. As a result, once a particular structure has been attained based upon appropriately designed DNA, core compositions and sizes can be selected to create structurally similar colloidal crystals with photonic, plasmonic, optical, mechano-optical, or catalytic properties that derive from the particle building blocks and crystal symmetry and habit of the targeted structure. (3,212)
Highly periodic colloidal crystals composed of plasmonically and photonically active nanoparticles are particularly well-suited for optical applications, as they interact with light in ways that most natural materials cannot. (212) For instance, the refractive indices of metal nanoparticle-based colloidal crystals depend on particle size, interparticle spacing, and crystal symmetry (Figure 5E). (25,231) The refractive index, in turn, determines stopband wavelengths and photonic bandgaps along specific crystallographic directions. (25) Moreover, three-dimensional colloidal crystals patterned onto substrates with defined Winterbottom orientations and exposed facets have been shown to function as micromirrors, guiding out-of-plane light along predictable paths. (232)
Colloidal crystals can also be designed as mechanical metamaterials. (233,234) Water accounts for a large portion of the volume of colloidal crystals engineered with DNA, so when evaporated, crystals completely collapse and lose their shape and crystallinity. (26) Remarkably, however, when the crystals are rehydrated, they return to their original, faceted morphologies (with solidity and convexity shape parameter values returning to 1 for rehydrated crystals from values as low as 0.83 for dehydrated crystals); this behavior is notable. No conventional crystals are able to undergo such severe deformation without irreversible damage, but DNA sequence programs structural information, ensuring high-fidelity recovery of colloidal crystal structure and function even after hydrogen bond breakage. The dramatic structural change (unit cell contraction from 22.1 to 16.4 nm in bcc lattices with 5 nm AuNPs) between intact and collapsed colloidal crystal structures leads to refractive index changes that produce different optical absorption and reflection properties that can be reversibly accessed based on hydration state (Figure 5H). Other chemical stimuli including intercalators (235) and multivalent cations (236) have been used to dynamically alter crystal structure. In one example, the addition of Ni2+ resulted in a fast and reversible reduction in crystal volume by over 65%. (236) These examples show that crystals engineered with macromolecular bonds may be useful as stimuli-responsive, mechanical metamaterials with properties that exceed those in natural materials.
Colloidal crystals can also be designed as heterogeneous catalysts, where nanoscale porosity and structure established by DNA-mediated interactions are maintained even after postsynthetic modifications. (237,238) For example, gold nanoparticles assembled into a bcc lattice with DNA were stabilized with silica and calcined, creating a porous, catalytically active material for alcohol oxidation (Figure 5F). (24) In another case, metal-organic framework (MOF) nanoparticles (PCN-222) were used as the cores of PAEs, introducing a novel class of porous PAE that synergistically combines the functionalities of MOFs and SNAs. (239) These PAEs were then assembled into colloidal crystals via programmable DNA interactions, and the resulting colloidal crystals catalyzed a selective oxidation reaction with increased catalytic conversion efficiency compared to MOFs not structured in a colloidal crystal.
III.ix. Scientific Discovery: Face-to-Face Bonding Driving Crystallization through the Complementary Contact Model. Engineering Outcomes: Expanding Structural Possibilities for Optically Active Colloidal Crystals Engineered with DNA
The ability to synthesize anisotropic SNA analogues, composed of rods, rhombic dodecahedra, and triangular prisms, permitted new insights into the CCM. (93) With isotropic PAEs, like SNAs, the number of favorable DNA interactions along any given direction is essentially the same, whereas with anisotropic PAEs, the number of favorable DNA interactions along any given direction is not the same; more binding interactions will be possible along certain directions, dependent upon shape (within the zone of anisotropy). (92) Thus, the CCM as applied to anisotropic PAEs gives rise to directional binding interactions that are driven by particle facets. Indeed, face-to-face bonding maximizes hybridization interactions between large, flat facets with more dense arrangements of DNA (Figure 5B). (92) For example, gold triangular nanoprisms form 1D lamellar stacks, (93) and gold rhombic dodecahedra form well-ordered fcc colloidal crystals through face-to-face interactions between their large triangular faces and rhombic [110] faces, (93) respectively.
The use of anisotropic PAEs in colloidal crystal engineering with DNA has opened a vast design space to access new classes of functional, programmable matter on the nanoscale. Space-filling metacrystals composed of nanocubes were designed and prepared with high refractive indices (∼8) and tunable Mie resonances dependent on crystal habit size. (240) Because the DNA hybridization events direct the assembly and crystallization of nanoparticles, even nonspace-filling nanoparticle shapes can be used as building blocks for intricate symmetries and materials. (105) For example, colloidal dodecagonal quasicrystals were accessed via face-to-face DNA bonding interactions between the triangular facets of 5-fold symmetric decahedral nanoparticles. (214) Notably, in contrast, decahedral nanoparticles assembled via slow evaporation formed only a densely packed, triclinic structure without facet registry. Low-symmetry lattices were realized using octahedral PAEs designed to maximize face-to-face interactions through DNA bonding to form noncentrosymmetric metacrystals with nonlinear optical behavior (second harmonic generation, SHG). (241) PAEs with gold bipyramidal nanoparticle cores were used to prepare Kagome lattices, where light was selectively emitted from different crystallographic directions. (242) These examples highlight the advantage of DNA-directed, face-to-face bonding in combination with nanoparticle geometry to predict, program, and synthesize colloidal crystal symmetries not possible with other methods.
Anisotropic nanostructures in colloidal crystal engineering with DNA have also allowed scientists to engineer a variety of optical metasurfaces. Nanocube arrays have been prepared with tunable optical reflection properties by coupling plasmonic gap modes and photonic modes, controlled through particle-to-metal substrate distance (established by DNA length) and periodic spacing between particles, respectively (Figure 5G). (243) In another case, gold nanocubes on gold thin films were used to create plasmonic nanoantennas that control fluorescent emission. (244) In this system, dye-modified DNA directed the assembly of the gold particles on the surfaces, and the dye served as the functional emitter plasmonically coupled to the cavity for tunable and stimuli-responsive fluorescence. Metasurfaces comprised of anisotropic, plasmonic PAEs have been engineered to have high refractive indices by organizing them in face-to-face or corner-to-corner orientations with finely tuned interparticle spacings that maximize capacitive coupling. (245) Furthermore, when this 2D superlattice is coupled to a gold film underneath, the material exhibits epsilon-near-zero (ENZ) behavior, an optical condition that can be leveraged to efficiently manipulate electromagnetic waves.
III.x. Scientific Discovery: Edge-Bonding Driving Crystallization of Hollow, Nanoframe Materials via Complementary Contact Model. Engineering Outcomes: Variety of Interesting Optical and Mechanical Colloidal Crystals
Noble metal nanoframes and nanocages were recently prepared and used as hollow building blocks for porous colloidal crystal structures. (106) Based on the CCM, researchers found that the assembly of these hollow PAEs relied on maximizing edge-bonding (Figure 5C). (206) Edge-bonding was also found to permit the crystallization of nonspace filling polyhedra, which led to the introduction of stable, nanoscale voids in colloidal crystal lattices engineered using DNA. Such an arrangement is not possible to achieve with solid polyhedral nanoparticles that do not tile in space because face-to-face bonds dominate particle interactions, preventing void formation of such shapes and dimensions. The control of nanoframe facet and nanocage thickness can be used to engineer the colloidal crystal porosity and topology; even materials with the same symmetry (e.g., simple cubic) can be synthesized with different pore shapes based on the topology of the nanoparticle building block (cubic nanoframe vs cubic nanocage). Such porous or hollow PAE colloidal crystals with pore sizes (between 10 and 1000 nm) that bridge the molecular and macroscales are useful in catalysis, (24) separations, storage, or optics. (241,246)
Open-channel colloidal crystals composed of nanoframes and nanocages have led to new types of structural outcomes that cannot be realized with the analogous filled structures. For example, monolayers of plasmonic octahedral nanoframes (200 nm thickness) functioned as broadband light absorbers (wavelengths from 400 to 800 nm) compared to monolayers of solid octahedral nanoparticles. (247) Open-channel architectures have also been constructed as mechanical metamaterials that exhibit unusual mechanical strength that is highly dependent on the nanoparticle building blocks (solid, partially open, and open nanoframe). (248) For example, colloidal crystals with truncated cubic nanoframe building blocks have high specific strength (124 MPa/g cm–3) compared to those constructed with nanocages or solid particle counterparts (23 and 19 MPa/g cm–3, respectively), a property that arises from nanoscale strain hardening effects and lattice densification that are afforded by unit cell design. Finally, a superlattice with cubic-close-packed crystal symmetry composed of octahedral nanoframes was identified as a material with negative refraction, an optical property not found in natural materials that can be used in optical cloaking. (206)
IV. Conclusions
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This case study of the spherical nucleic acid architecture highlights how synthetic advances and fundamental discoveries at the nanoscale have driven transformative engineering outcomes. SNAs were originally envisioned as a route to the construction of programmable colloidal crystals, where the DNA component solved both the scale and cross-reactivity issues associated with small molecules being used at the time. From there, SNAs have spurred a new way of thinking about chemistry, one centered on the “nanoparticle” atom and the nucleic acid “bond.” (249) Based on this new class of nanoscale building blocks, SNAs evolved into a versatile platform with broad uses in molecular diagnostics, therapeutics, materials science, and advanced manufacturing. The development of new SNA synthons and the discoveries of their characteristic properties, such as their distance-dependent optical properties, cooperative binding behavior, catalytic capabilities, and rapid cellular uptake, have enabled innovations like ultrasensitive biosensors, state-of-the-art gene regulatory and immunomodulatory nanomedicines, and programmable metamaterials. These innovations emerged directly from development in synthetic capabilities and fundamental chemistry that elucidated nanoscale structure–function relationships that were sometimes unexpected.
The inherent modularity and chemical versatility of SNAs portend that, even after almost three decades, synthetic innovation will continue to drive SNA research forward. The integration of artificial intelligence and machine learning will accelerate the exploration of increasingly complex, next-generation architectures such as optically active microcrystals for computing hardware, biological labels, and structural nanomedicines. (8,9)
The realization of molecularly precise, monodisperse nanoarchitectures will drive future work, in part because they will enable unambiguous determination of the exact (rather than average) structural relationships that underpin function. By providing this foundation, synthetic advances will produce powerful tools for driving scientific discovery in two key areas: first, in understanding and designing crystallization pathways to access kinetic and nonequilibrium crystal products; and second, in probing SNA interactions at the cellular and organismal levels to enable the design of more effective life science tools and nanomedicines.
Ultimately, SNAs model a powerful synthesis–discovery–invention cycle. Researchers should consider applying this approach to other nanoscale systems, leveraging design, synthesis, and fundamental knowledge-building to address emerging engineering and technological challenges.
Author Information
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- Chad A. Mirkin - Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, Illinois 60208, United States; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;
https://orcid.org/0000-0002-6634-7627;
- Connor M. Forsyth - Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, Illinois 60208, United States; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;https://orcid.org/0000-0002-2576-861X
- Rachel R. Chan - Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;https://orcid.org/0000-0001-7034-9513
- Tanner D. Fink - Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;https://orcid.org/0000-0003-2102-3220
- Janice Kang - Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;https://orcid.org/0009-0007-0837-2406
- Jacob D. Cohen - Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, Illinois 60208, United States; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;https://orcid.org/0000-0003-4961-1905
- Sarah Hurst Petrosko - Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;https://orcid.org/0000-0002-7319-3232
CRediT: Connor M. Forsyth conceptualization, project administration, visualization, writing - original draft, writing - review & editing; Rachel R. Chan conceptualization, visualization, writing - original draft, writing - review & editing; Tanner D. Fink conceptualization, visualization, writing - original draft, writing - review & editing; Janice Kang conceptualization, visualization, writing - original draft, writing - review & editing; Jacob D. Cohen visualization; Sarah Hurst Petrosko conceptualization, supervision, writing - original draft, writing - review & editing; Chad A. Mirkin conceptualization, formal analysis, funding acquisition, investigation, supervision, writing - review & editing.
Biographies
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Connor M. Forsyth
Connor M. Forsyth is an M.D./Ph.D. candidate in the Medical Scientist Training Program at Northwestern University, advised by Profs. Chad A. Mirkin and Alexander H. Stegh. He holds a B.S. in Molecular and Cellular Biology from the University of Illinois (2018) and an M.S. in Biotechnology from Northwestern University (2020). His research focuses on developing nanomedicine-based immunotherapies and investigating their fundamental interactions with biological systems.
Rachel R. Chan
Rachel R. Chan received her B.S. in Chemistry from the University of California, Berkeley (2021). She is currently pursuing her Ph.D. in Chemistry under the guidance of Prof. Chad Mirkin at Northwestern University. Her research focuses on designing defects into colloidal crystals engineered with DNA and integrating nanoparticles into larger, nanophotonic structures.
Tanner D. Fink
Tanner D. Fink received his B.S. degree in Chemical Engineering from Iowa State University (2016) and Ph.D. in Chemical Engineering from Rensselaer Polytechnic Institute (2022). Now, he is an International Institute for Nanotechnology Willens Nano-oncology Postdoctoral Fellow under Prof. Chad Mirkin at Northwestern University. His research focuses on utilizing the spherical nucleic acid platform for the development of cancer vaccine technologies.
Janice Kang
Janice Kang received her B.A. degree in Chemistry from Hamilton College (2020) and is currently pursuing her Ph.D. in Chemistry with Prof. Chad A. Mirkin at Northwestern University. Her work integrates chemistry with structural nanomedicine for next-generation cancer immunotherapy.
Jacob D. Cohen
Jacob D. Cohen received his B.Scs. in Biochemistry and Neuroscience from Indiana University Bloomington (2018). He is currently a Ph.D. candidate under the supervision of Prof. Chad A. Mirkin at Northwestern University. His work primarily focuses on studying nanoscale vaccine processing kinetics using spherical nucleic acids and the development of breast cancer therapeutics.
Sarah Hurst Petrosko
Sarah Hurst Petrosko received B.S. degrees in Chemistry and in Physics from the University of Florida in 2003 and a Ph.D. in Chemistry from Northwestern University (NU) in 2009. She is currently a Research Professor in the Department of Chemistry at NU and the Associate Director of NU’s International Institute for Nanotechnology.
Chad A. Mirkin
Chad A. Mirkin obtained his B.S. degree in 1986 from Dickinson College and his Ph.D. in 1989 from The Pennsylvania State University. He joined Northwestern University as an Assistant Professor in 1991. He currently serves as the Director of the International Institute for Nanotechnology and a Professor of Chemistry, Materials Science and Engineering, Biomedical Engineering, Chemical and Biological Engineering, and Medicine at Northwestern University. He is the inventor and developer of spherical nucleic acids as well as several additive manufacturing, nanopatterning, and materials discovery methodologies (including Dip Pen Nanolithography, Polymer Pen Lithography, Beam Pen Lithography, and High Area Rapid Printing), and he has cofounded 11 companies. Professor Mirkin has been elected to all three U.S. National Academies, as well as the American Academy of Arts and Sciences. He cofounded the journal Small, and has served on the editorial advisory boards of more than 35 scholarly journals.
Acknowledgments
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Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Awards R01CA257926 and R01CA275430 and the Research Development Program under P50CA221747. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This manuscript is the result of funding in whole or in part by the National Institutes of Health (NIH) and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH. This material is also based upon work supported by the Air Force Office of Scientific Research Award FA9550-22-1-0300, the Lefkofsky Family Foundation, and Edgar H. Bachrach through the Bachrach Family Foundation. R.R.C. was partially supported by the National Science Foundation Graduate Research Fellowship Program Grant DGE-2234667. J.D.C. was partially supported by the Department of Defense through the National Defense Science & Engineering Graduate (NDSEG) Fellowship Program. C.M.F. was partially supported by a research grant from the Melanoma Research Foundation. Molecular graphics were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. Some figures were created with BioRender.
References
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Abstract
Figure 1
Figure 1. Synthetic advances with SNAs. (A) Schematic shows a gold-core SNA radially functionalized with strands of oligonucleotides. (B) SNAs exhibit a high degree of oligonucleotide and core shape modularity. Functional oligonucleotides typically contain three segments: a functional oligonucleotide sequence, a spacer segment, and an attachment group for nanoparticle surface binding. SNA-like properties can be achieved using anisotropic nanoparticle cores including truncated octahedron, truncated octahedral nanoframes, cubes, and triangular prisms. Adapted with permission from ref (206). Copyright 2022 Springer Nature Ltd. (C) SNA diameter is dependent on the core size and oligonucleotide shell length. Both parameters can be tuned independently. SNAs of the same diameter can be prepared using different core sizes and DNA shell lengths. Adapted with permission from ref (10). Copyright 2011 American Association for the Advancement of Science. (D) To date, SNAs have been synthesized using a variety of core materials that allow access to vastly different physicochemical properties. Core materials have included both inorganic and organic cores, and they endow the SNA structures with specific properties (e.g., plasmonic and enzymatic) based on composition. Pictured are a selection of different SNAs with a diversity of core materials, including molecular, protein, gold, liposomal, and lipid nanoparticle cores ranging in size from ∼1 to >150 nm. The representation of a CRISPR SNA is adapted from PDB ID 8UZA. ePMV software was used in the generation of panels A, B, and D, ref (250).
Figure 2
Figure 2. Fundamental research and engineering development with SNA-based probes. (A) Solutions of gold nanoparticle-core SNAs before (left; dispersed particles are red) and after the addition of a target DNA sequence links the SNAs (right; aggregated particles are purple). (B) Melting curves show free DNA and the same DNA attached to a gold-core SNA and a core-free polyvalent nucleic acid nanostructure (PNAN) (left); enthalpies and entropies of DNA hybridization to linear DNA and SNAs are derived from a concentration-dependent fluorescence hybridization assay (right). Panel B, left: Adapted with permission from ref (59). Copyright 2011 American Chemical Society. Panel B, right: Reprinted with permission from ref (131). Copyright 2018 American Chemical Society. (C) Example shows polynucleotide target detection using the colorimetric Northwestern Spot Test (left). Solutions of SNA probes were mixed with a fully complementary target strand (Target), without the target (No Target) and with a target contaning a single base pair mismatch (Mismatch Target) and heated to the indicated temperature. Note the high degree of discrimination between the fully complementary and mismatched targets, allowing for the detection of single nucleotide mismatches. Example shows the first SNA-based scanometric detection system wherein oligonucleotide arrays were treated with target strands (either fully complementary [A] or with a single base pair mismatch, substituting A for G, T, or C) and SNA probes were developed at the indicated temperatures (right). Panel C, left: Adapted with permission from ref (112). Copyright 1997 American Association for the Advancement of Science. Panel C, right: Reprinted with permission from ref (126). Copyright 2000 American Association for the Advancement of Science. (D) Chip-based multiplexed scanometric detection of barcode-DNA strands are released from SNA probes after incubation with DNA targets derived from the human immunodeficiency virus (HIV), Ebola virus (EV), variola virus (VV), and hepatitis B virus (HBV), or a mixture of all four (Mix). Adapted with permission from ref (139). Copyright 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. ePMV software was used in the generation of panel A, ref (250).
Figure 3
Figure 3. Scientific discoveries and engineering outcomes of SNAs in nanomedicine research. (A) The dense 3D DNA shell of SNAs confers enhanced resistance to nuclease degradation relative to linear oligonucleotides. This protection arises from slower enzymatic hydrolysis, as the negatively charged and sterically bulky shell inhibits nuclease activity. The protein corona that forms on SNAs in biological media is not depicted. FAN1 Nuclease PDB ID 8S5A. (B) Compared to linear or transfected oligonucleotides, SNAs exhibit high cellular uptake due to their multivalent interactions with class A scavenger receptors, which facilitate endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. The representation of scavenger receptors is adapted from PDB IDs 2QIH and 7DPX. (C) Their high uptake efficiency, stability, and limited activation of host immune responses enable SNAs to function broadly as tools in both in vitro and in vivo systems. This versatility supports their use in intracellular detection, imaging, gene regulation, and immunotherapy. (D) Detection probes, including nanoflares, sticky-flares, and FIT-flares, have been engineered to sense intracellular RNA, ions, small molecules, and diseased tissue in vivo, as well as to perform live-cell genetic and metabolic analysis. These probes incorporate fluorophores that are either released or activated upon target binding, generating sensitive and responsive readouts. (E) As gene regulation agents, SNAs can be constructed from DNA or RNA to modulate expression through antisense or RNA interference pathways. As immunotherapies, they stimulate both innate and adaptive immune responses and have shown promise as nanomedicines for treating diverse cancers and infectious disease. The representation of a CRISPR SNA is adapted from PDB ID 8UZA. ePMV software was used in the generation of panels A, B, D, and E, ref (250).
Figure 4
Figure 4. Fundamental research and engineering development with SNA-based immunotherapeutics. Key scientific discoveries such as (A) the multivalent display of CpG DNA on SNAs potently stimulating TLR9 have pioneered the new field of structural immunotherapy. The representation of TLR9 is adapted from PDB IDs 5Y3M and 6US8. (B) Compositionally identical yet structurally distinct SNAs suppress tumor growth differentially, demonstrating the importance of nanoarchitecture in next-generation therapeutic development. Adapted with permission from ref (6). Copyright 2019 National Academy of Sciences. (C) These structure–function relationships extend to more complex therapeutics. The differential placements of MHC-I- and MHC-II-restricted antigens in DA-SNA 1 and 2 substantially alter tumor suppression. Adapted with permission from ref (22). Copyright 2023 Springer Nature Ltd. (D) The oligonucleotide shell of SNAs dictates their circulation and biodistribution, leading to the discovery of new agents that cross the blood–brain barrier (BBB). (E) Gold SNAs bearing Bcl2L12 siRNA labeled with Gd(III) localize in glioma tumor tissue following intracranial injection as shown in magnetic resonance (MR) images (top), hematoxylin and eosin-stained brain sections (middle), and the 3D reconstruction of MR data (bottom). Reprinted with permission from ref (195). Copyright 2013 American Association for the Advancement of Science (AAAS). (F) β-galactosidase-based ProSNA functionalized with transferrin aptamer (upper left) successfully accumulates within the brain (lower left), quantified by radiant efficiency (right). Reprinted with permission from ref (41). Copyright 2022 American Chemical Society. ePMV software was used in the generation of panels A, B, and C, ref (250).
Figure 5
Figure 5. Scientific discoveries, materials design, and engineering outcomes through the crystallization of SNAs and other types of programmable atom equivalents (PAEs). (A) The colloidal crystal design space arises from the synthetic advances in SNA preparation, where enthalpy-dominated DNA interactions direct crystallization. Metal nanoparticle core (shape and size) and DNA design determine the lattice symmetry and crystal habit. Scale bars = 125, 75, and 1000 nm from left to right. (B) Enthalpic DNA bonding interactions are maximized with facet registry between anisotropic nanoparticle cores, such as cubes. Scale bar = 500 nm. (C) DNA bonding is maximized along the edges of nanoframes, forming a crystalline symmetry from a non-space-filling polyhedral. Scale bar = 1 μm. Reprinted with permission from ref (206). Copyright 2022 Springer Nature Ltd. (D) Thin films and Winterbottom constructions can be formed from heterogeneous crystal growth on substrates. Reprinted with permission from ref (226). Copyright 2017 American Chemical Society. (E) The refractive index of colloidal crystals can be designed as a function of NP shape, NP size, volume fraction, and symmetry. Reprinted with permission from ref (206). Copyright 2022 Springer Nature Ltd. (F) Colloidal crystals components can be stabilized and used as heterogeneous catalysts. (G) Deterministic placement is shown for single PAEs to couple photonic response (determined by spacing, P) and plasmonic response (distance between Au cube and Au substrate). Reprinted with permission from ref (243). Copyright 2015 American Chemical Society. (H) Colloidal crystals exhibit shape memory upon dehydration and rehydration. The mechanical response of the colloidal crystal due to a reversible change in refractive index results in tunable optical response. ePMV software was used in the generation of panel A, ref (250).
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