1 Introduction

In natural systems, biopolymers cooperatively assemble and interact at the nanoscale to form microscale structures. For example, the diploid human genome contains approximately 3 billion DNA base pairs. Based on the canonical B-form DNA duplex (0.34 nm per base pair), the total length of DNA in each cell is about 2 m. How does such long DNA fit into the nucleus which is about 10 μm in diameter? The answer is DNA packaging. The assembly of chromosomal DNA is a highly regulated and hierarchical condensation involving many proteins. In eukaryotic cells, DNA packaging is an important process of wrapping DNA around histone proteins resulting in a hierarchical well-defined structure of compact DNA–protein complexes. This assembly procedure occurs at a broad of length scales from nanometer to micron scales, displaying organizational precision down to the angstrom level (Fig. 1).

Fig. 1
3 illustrations. 1. The double helix D N A base assembles into a chromosome pair. 2 and 3. The assembly at 0.1 nanometer atoms, 1 to 100 nanometers current self-assembly technology, and 1 to 100 micrometers cell organelles and cells, correspond to topics 2, 3, and 1, in order.

DNA assembly happens at multiple scales in nature. Current DNA nanotechnology has several challenges and opportunities to be expanded in ‘depth and breadth.’ Three selected topics will be discussed here: (1) Engineering cell-sized DNA structures; (2) Building self-assembled DNA crystals with atomic resolutions; (3) Transferring to RNA structural design

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Towards the goal of engineering bioinspired systems that rival natural systems, information-coding biopolymers such as nucleic acids [1,2,3], proteins [4,5,6], and lipids [7] have been used as building blocks in the assembly of designer nanoarchitectures and nanodevices. Among them, DNA self-assembly has been broadly exploited [8,9,10,11,12,13], and diverse design techniques [3, 14,15,16,17] and computational tools [18,19,20,21,22,23,24] have been used, resulting in increased knowledge of building things with DNA as well as a wide variety of nanostructures. The success of DNA self-assembly in constructing various architectures is attributed to several reasons. Firstly, Watson–Crick base pairing between complementary DNA strands is simple and highly predictable and thus makes the four-letter polymeric strands convenient units with designed pairing rules between each other. Secondly, the geometric features of DNA double helices are well understood, with a diameter of about 2 nm and 3.4 nm per helical repeat for canonical B-form DNA [25]. Additionally, the development of several user-friendly software interfaces has facilitated the designing and viewing of even the most intricate DNA nanostructures before experimental testing [18,19,20,21,22,23,24]. Thirdly, modern organic chemistry and molecular biology provide a diverse toolbox to readily synthesize, modify, and replicate DNA molecules at a relatively low cost. Finally, the biocompatibility of DNA makes it suitable for constructing multicomponent nanostructures made from hetero-biomaterials with designed functions.

Inspired by nature, scientists keep turning to DNA nanotechnology to create structural designs that can also operate at various length scales. Here, I will share three examples that show how nanotechnology is moving closer to the goal of achieving precise structural control at the angstrom level within cells, as well as discuss some of the challenges that are involved. The first example focuses on the challenge of engineering programmable structures at the scale of entire cells. This is a significant obstacle, as it requires creating something microns in size from many individual nanoscale components through programmable interactions. The second example highlights the challenge of engineering the designer DNA crystals, which is the original vision for DNA nanotechnology. It has taken decades to achieve, but the process of its development has greatly expanded our understanding of molecular construction. Lastly, toward producing precision nanostructures inside of living cells, RNA is highly advantageous because it can be folded cotranscriptionally. Fortunately, the great progress in developing DNA nanostructures has accelerated the development of RNA nanostructures. Nucleic acid nanotechnology, originally drive by curiosity, has greatly informed our understanding of structural biology and now has produced many exciting future applications.

2 Engineering Cell-Sized DNA Structures

It is a challenging yet rewarding goal in DNA nanotechnology to make cell-sized structures because such materials have several potential applications that cannot be realized by smaller structures. For example, DNA origami [3] is a technique to fold a long single-stranded ‘scaffold’ DNA to a target object using hundreds of short ‘staple’ DNA strands. This technique was first introduced in 2006 and has been employed in many works. The DNA origami nanostructures generally show 10–100 nm in diameter and are great scaffolds to host a few enzymes or quantum dots due to their compatible sizes. Similarly, micron-sized constructs with defined shapes and finite sizes  will provide a fully addressable canvas to organize larger guests with nanoscale precision. Those constructs will be able to organize larger targets, such as cells, and offer long-range interactions between guest molecules that cannot be achieved by previous small structures. The micron-sized 2D arrays can serve as high-throughput biological nanopore arrays for protein sequencing and biosensing. They can also be used as templates for creating long-range enzyme cascades/signaling, modulating cell-free membrane, and eventually facilitating artificial cell engineering.

2.1 Challenges

Although various strategies have been developed to produce synthetic DNA architectures that exhibit significant geometric complexity, most current techniques are still limited to produce DNA structures smaller than 1 micron at few nanometer resolutions. To create larger DNA constructs with defined shapes and finite sizes, different strategies have been reported. Qian and coworkers advanced higher-order assemblies by using 2D square-shaped DNA origamis with surface patterns and short sticky ends hybridization to create a finite-sized 2D DNA canvas of sizes up to half micron [26]. 3D DNA origami higher-order structures are achieved by using an angle-controllable V-shaped DNA origami object to form several polyhedrons that are up to 450 nm in diameter [27]. The single-stranded tile (SST) DNA structures are also advanced to larger assemblies employing a brick design of 52-nt long with four 13-nt domains [28]. The 2D and 3D origami-based strategies seek week interactions between building blocks and employ a step-by-step hierarchical assembly process that typically involves the formation and purification of individual origami, assembly of sub-units from a set of origami blocks, and the addition of origami blocks for final constructions. However, there are challenges associated with these methods. The first challenge lies in designing DNA origami that can self-assemble into micron-sized structures. The individual origami needs to be accurately designed because any twist or distortion in these units will accumulate and become amplified during the higher-order assembly process. Another challenge is the low formation yield. Potential reasons for the low yield include the possible defects in individual origami building blocks and the slow kinetics of origami higher-order assembly. For the SST method, a new challenge is the importance of sequence besides the accurate geometric design since there is no scaffold sequence as a guidance in the structures. In addition, the low formation yield, as well as the high synthesis cost, also contributes to the difficulty of using this method to create even larger structures.

For the formation of 2D and 3D DNA superlattices, DNA origami nanostructures serve as repeating units to hierarchically connect into higher-order assemblies. Inspired by the first rationally designed DNA crystal structure [16], Liedl and coworkers created an origami version of the tensegrity triangle and demonstrated the assembled rhombohedral crystalline lattices [29]. Several examples showed that weak interaction will help the mismatched DNA origami units to dissociate from each other during assembly and thus promote the formation of correct target patterns [26, 30]. One challenge is the accurate estimation of the mechanical properties of DNA structures. For instance, the formation of large 2D arrays generally suffers from the inherent flexibility of individual building blocks. It is important to develop methods for confining the assembly process to one plane, rather than in 3D, to grow 2D crystalline assemblies. Surface-mediated growth is also a helpful strategy to encourage the 2D arrays development including using lipid [31, 32] and mica surfaces [33]. Recently, Gang and colleagues reported a novel technique of creating vertex-to-vertex hybridization between polyhedral DNA origami building blocks [34]. Instead of avoiding flexibility, they explored single-stranded loop linkers between origami, relied on the geometric restriction, and harnessed the flexibility of the loops. This vertex-to-vertex hybridization is remarkably robust and programmable being able to form a wide variety of polyhedral geometries. Although the DNA origami crystalline lattices do not have the similar atomic resolution as designer DNA crystals, these higher-ordered arrays provide much larger cavities for hosting various guest molecules such as large enzyme complexes.

2.2 Opportunities

Although a variety of design techniques have been developed, it is desirable to further enrich the types of DNA building blocks with novel structural properties that enable efficient scale-up of DNA assemblies. New design strategies combined with mathematical graphics will provide additional opportunities for DNA nanoconstruction and enhance out understanding of DNA self-assembly as a programmable biomaterial. Advanced experimental validation techniques are also valuable for revealing the assembly dynamics at the individual unit level. In addition, it is highly desirable to develop simple yet robust procedures to improve the mechanical properties of DNA nanostructures, while preserving their nanometer precision and dynamic features such as strand displacement reactions [35, 36].

A key opportunity is to utilized hybrid assembly methods, which involve combining multiple types of building block materials and leveraging different interactions between building blocks. The co-assembly of DNA polyhedral origami and gold nanoparticle is a great example of this approach, showing the potentials for superlattice construction. In order to ensure appropriate binding forces between assembly building blocks for orthogonal regulation of assembly structures, a wide variety of binding forces should be investigated, ranging from weak interactions such as base stacking and sequence recognition to strong chemical bonds through click chemistry and enzyme ligation. The utilization of different binding forces will help to create a local energetic maximization of stability, while maintaining weak interactions between assembly units. The local optimization of the recognition between building blocks will promote the formation of target structures, and the weak interactions will minimize any possible mismatch. More importantly, integration of orthogonal interaction forces between assembly units could potentially facilitate sophisticated assembly behaviors such as dynamic or developmental self-assembly behaviors observed in living cells [37].

The possible successful formation of micron-sized programmable DNA structures with nanometer precision promises many new opportunities for both fundamental and applied research. Micron-sized DNA assemblies with fully addressable surfaces will enable various types of synthetic cell engineering by employing structural DNA assemblies as spatial frameworks. DNA nanostructures equipped with membrane-interacting molecules have been demonstrated as nanoscale mechanical tools to scaffold and sculpt lipid bilayer [38, 39]. Large DNA assemblies will contribute to the creation of artificial cells with comparable sizes as living cells and deliver a unique interface between cell biology and biomolecular engineering.

3 Building Designer DNA Crystals with Atomic Resolutions

Crystal lattices with atomic resolution are useful materials for positioning guest molecules at specific locations within three-dimensional space to achieve various functions. Obtaining self-assembled nucleic acid crystals with programmable space groups and cavity sizes is not only a long-standing challenge in DNA nanotechnology but also one of the important research frontiers. As the original idea proposed by Nadrian Seeman in 1982 [1], introducing target molecules into the DNA scaffolds will facilitate structure determination of guest molecules such as RNA, peptide, and protein. Rational design and synthesis of 3D DNA crystals provide both precisely designed symmetry and functions. Such crystals can serve as porous scaffolds to arrange guest molecules at specific positions, and thus the guest molecules could be integral parts of the crystalline lattices. Those hybrid crystalline structures can be selected as novel candidates for the determination of protein structures, especially for membrane proteins. Self-assembling DNA crystals have also been treated as 3D templates for molecular electronics, such as information storage devices and zeolite-like nanoporous materials that are capable of catalysis [40] and molecular separations [41].

3.1 Challenges

However, after four decades of the initial proposal [1], only a few self-assembled DNA crystals have been reported displacing rationally designed 3D crystalline structures. In 2009, Seeman, Mao, and their coworkers created the first rationally designed DNA crystals that were based on a tensegrity triangle DNA motif, demonstrating a set of crystals in the rhombohedral space group R3 [16]. These are the first-ever designed self-assembled DNA crystals, which are published 29 years after Dr. Seeman’s initial inspiration [42]. In 2016, Yan, Seeman, and coworkers reported a new designer DNA crystal based on a layered Holliday junction design with three distinct strands, solving the structure by X-ray crystallography to ~3 Å [43]. Later, a rationally designed and self-assembled 3D DNA crystal lattice with hexagonal symmetry was successfully created by using only two DNA strands. The six-fold symmetry, as well as the chirality of the crystal lattices, is directed by the Holliday junctions formed between the duplex motifs. Native crystals were measured and analyzed to ~3 Å resolution with the hexagonal space group P6 [44].

The main scientific challenges for creating designer DNA crystals lie in both fundamental design and experimental growth of such crystals. Three questions will be discussed including how to develop robust design methods for creating a wide variety of designer DNA crystals with prescribed lattices, how to introduce guest molecules into crystals at specific locations, and how to enable DNA crystals to have better chemical/physical/mechanical properties better suited to broader applications.

To create 3D DNA motifs that can be connected by rational designed sticky end connections rather than through nonspecific stacking, various factors should be examined deliberately. The designer DNA crystals should be assembled from rigid tiles/motifs with appropriate numbers of sticky ends. The individual DNA tile needs to be designed with sufficient connections to define the structural frame, and the interactions between tiles should be encoded into sticky ends. The sequence design of DNA tiles should be investigated thoughtfully. The DNA motifs are formed through an annealing process, where a slow temperature ramp is needed. A systematic crystallization protocol needs to be established to incorporate the annealing process with the crystallization process as well as the experimental conditions to improve the yield of large crystals, including buffer conditions, reservoir conditions, and annealing temperatures. X-ray crystallography will be the major technique used to determine the crystalline structures of DNA crystals. As X-ray requires relatively large sizes of crystals, other techniques, such as micro-electron diffraction (Micro-ED), can be employed to solve the structures of nanocrystals.

Self-assembled DNA crystals contain large cavities that make them excellent scaffolds for attaching various biomolecules (e.g., peptides, proteins, and RNAs) to achieve different functional applications. The major hurdles to adding guest materials into designer DNA crystals are two-fold. First, the binding of the DNA and guest molecules shouldn’t change the space groups of the predefined 3D crystal lattices, and the guest molecules can be only arranged in the appropriate cavities of the designer crystals. Second, the interaction between the DNA lattices with the guest molecules should be robust and specific, so that the guest molecules can be treated as an internal part of the crystal lattices with atomic-level precision for further applications. For these two main challenges, one simple solution is to use sequence-specific DNA binding peptides or proteins as the guest molecule. The interactions between DNA and peptides/proteins are highly specific and strong, which exists naturally and doesn’t need artificial linkers between DNA and proteins. Another advantage of using DNA binding peptides as the guest molecules is that these types of proteins generally have small sizes and can easily diffuse into the cavities of a crystal. Therefore, we can separate the experimental steps between the growth of the designer DNA crystals with the soaking of target DNA binding peptides/proteins, so that the crystal lattices can be preserved after introducing guest proteins. Another exciting prospect is constructing DNA/RNA and RNA/RNA self-assembled crystals by incorporating RNA strands into the DNA crystals and adapting a DNA motif design to create RNA motifs. These hybrid crystalline materials will provide new applications in many areas, such as assisting the structural determination of small RNA structures, building molecular devices from functional RNA motifs, and studying the RNA–protein interactions.

3.2 Opportunities

In addition to expanding the structural diversity of designer DNA crystals, one interesting topic is generating unconventional states of materials [45], such as quasicrystals and disordered hyperuniform DNA structures, in a controllable and programmable fashion. The mathematic description and simulation of using patch particles to create quasicrystal patterns were reported [46] before the experimental realizations [47]. The well-studied DNA multi-arm junction tiles make them ideal model systems to conduct programmable self-assembly in 2D. Rational designed 3D quasicrystals using DNA tiles remain a challenge. Computational simulations using 3D particles were reported [48], and designer DNA quasicrystals are likely to be achieved in the foreseeable future. Other states of matter that have been introduced in recent years can be new design targets for engineering bioinspired and biomimetic systems in DNA nanotechnology. Such studies will enrich the types of programmable functional biomaterials, establish the structure–function relationship for unconventional states of materials, and gain knowledge of fundamental self-assembly in such systems.

The creation of DNA crystalline scaffolds with atomic resolution will provide precise spatial programmability of molecules, offering many application opportunities for various research areas. For example, it is useful to create a 3D network of enzyme cascades or energy transfer pathways based on chromophores with accurate location and orientation by employing DNA crystal templates. 3D DNA crystals also serve as zeolite-like/nanoporous materials that are capable of catalysis and molecular separations. In addition, some applications require intimate knowledge of the atomic-level details of DNA structures, and the designer DNA crystals can provide such information. Although researchers have obtained cryo-EM reconstructions for various DNA complexes and revealed the structures of DNA complexes with nucleotide resolution [49, 50], universal strategies are not established yet for creating different types of designer DNA crystals. For instance, there is no crystal structure of the double crossover (DX) tile that existed in most DNA nanostructures including DNA origami. Consequently, the deformation near crossovers introduced by adding the crossovers, and the base-level sequence impact of DNA structures are still unknown. Angstrom-level positioning accuracy at the scale of individual DNA bases will enable new opportunities such as chromophore placement on DNA-dye assemblies. Structural information gained from crystals can be used to improving DNA designs, leading to a greater understanding of DNA as a biomaterial.

The potential applications of DNA crystals extend beyond their use as scaffolds for crystallization. One example is using crystalline complexes as molecular ‘sponges’ to detect or separate target molecules by trapping or binding them in the cavities. To expand the scope of DNA lattices to other fields—especially ones where biological materials may not be stable—integrating designer DNA crystals with other materials will be highly desirable. For example, it is possible to introduce inorganic materials growing along DNA helixes, so that the resulting products will inherit the programmable geometric feature of DNA crystals. Like the biomineralization process, inorganic materials, such as silica, can be deposited on the surface of DNA. Our recent study revealed that silica-DNA composited structural nanomaterials with a set of controllable morphologies can be created using chemical reactions [51]. This technique was further developed to cost silica shell on 3D origami lattices [52] and to create superconducting 3D materials with another layer of niobium coating on top of silica layer [53]. This technique has the potential to be adopted into designer DNA crystals as well. One challenge is how to allow the depositing materials to permeate the 3D crystals through their relatively small cavities. The resulting porous materials should exhibit significantly improved mechanical properties due to the inorganic coating. By transferring the structural programmability of designer DNA crystals to inorganic materials, the nucleic acid-based concreating strategy will open exciting opportunities for novel nanofabrication with various application potentials.

4 Transferring to RNA Structural Design

An important landmark in the development of nanotechnology was the use of biological molecules as building blocks to construct devices with control of structures and function at the nanometer scale. RNA, which shares some general features with DNA, has played a unique role. Unlike DNA, RNA has an inherent architectural potential to form a wide variety of interactions far beyond the Watson–Crick base pairing [54, 55]. As opposed to DNA, naturally existing 3D RNA molecules and man-made RNA building blocks/tiles [56, 57] at an atomic resolution can be modified and provide potentially a much larger toolkit to readily build a variety of structures with high complexity. In addition, functionalities associated with RNA molecules, such as catalysis [58], gene regulation [59], and organization of proteins in large machineries [60], enable their use in material and biomedical sciences [61]. Most importantly, RNA molecules can be readily synthesized in cells through transcription [62]. Therefore, RNA nanostructures have a great potential to build self-assembling nanodevices inside cells by utilizing the cellular nucleic acid synthesis pathway.

4.1 Challenges

Although RNA shares many general geometric and chemical features with DNA, the construction of custom RNA nanostructures has been hindered. For instance, it is still challenging to rationally designed RNA objects with comparable size and complexity to natural RNA machineries or current highly sophisticated DNA nanostructures. The emerging field of RNA nanotechnology has attracted increasing attention from diverse research areas in recent years, and many RNA nanostructures have been constructed, including squares [63, 64], tubes [65], arrays [66, 67], and 3D objects [68, 69]. In most studies, the use of conserved, naturally evolved motifs with predictable tertiary structures dominates the current RNA self-assembly methods. Natural RNA building blocks, called structural modules, can be combined and rearranged in a large number of ways into target shapes. But currently by using this method, the sizes of constructed RNA nanostructures are generally smaller than 200 nucleotides, and the complexity of RNA designs has been limited as well [70]. As a complementary approach, a de novo design strategy offers higher versatility, which allows us to build structures/functions that do not exist in nature but fulfill our needs. De novo designed RNA nanostructures have emerged recently. One example is a designed RNA nano-prism that self-assembled from eight T-shaped RNA motifs [71]. Those motifs have well-defined configurations and were created following the example of DNA T-junction tiles [72]. As compared with previous works that used naturally existing 3-way RNA junctions to construct polyhedrons [71], this de novo design method provides a unique way to control synthetic RNA structures, such as the angle, the length, and the sequence of target structures. A recent example of the T-shaped RNA tile is a single-stranded version named branched kissing loops [73]. 16 different linear and circular assemblies have been constructed from the tile by adjusting the tile geometry.

Self-folding of a single RNA chain into a defined complex nanostructure represents a new era in nucleic acid nanotechnology. Two-dimensional and unknotted folding of single-stranded RNA with 6300 bases long were demonstrated using thermal anneals [74]. Single-stranded RNA knots with 1000 nucleotides were reported by hierarchical folding in prescribed orders, exhibiting an unprecedented amount of complicated topological features [75]. One most exciting feature of RNA molecules is their cotranscriptional folding ability, which offers attractive potential applications for synthetic biology. The single chain of RNA folds itself during the transcription process in isothermal conditions in vitro and in cells. The rationally designed RNA assemblies with cotranscriptional folding provide a new avenue that could create self-assembled RNA scaffolds interfacing with synthetic biology and nanomedicine. Geary, Rothemund, and Andersen pioneered the RNA origami approach [67], enabling cotranscriptional assembly by arranging RNA helices parallelly through crossovers and kissing loops. Recently, the same team introduced RNA origami automated design software and extended the creation of large RNA tiles up to 2360 nucleotides [76], which represents the largest synthetic RNA structure that can be folded cotranscriptionally to date.

4.2 Opportunities

Since RNA structures began be characterized in higher resolution, the more we learn about RNA molecules, the more we realize how much we don’t know. There are a tremendous amount of knowledge and undiscovered rules for RNA structural and functional design. DNA nanostructures generally need annealing, a temperature cooling process, to promote the formation of designed Watson–Crick base pairs, leading to the minimal free energy (MFE) configurations. While natural RNA molecules don’t always fold into the MFE conformation [77, 78], the single-stranded RNA origami strategy [76] employs localized domain modules, optimizes MFE domains, and uses a multi-stage sequence optimization procedure to facilitate the isothermal folding. Considering the complexity of natural RNA structures and RNA folding, it is promising yet challenging to discover new design strategies. Inspirations could come from the unique features of RNA. For instance, RNA structural design allows us to harness the kinetic energy in RNA assembly. Near MFE configurations could be possibly achieved and stabilized through inserting local kinetic traps, adding protein binding regions, and topological constraints. Incorporating computational components into the RNA assembly process may also enable the creation of programmable dynamics. Particularly, in single-stranded RNA folding, we can imagine that inserting intramolecular strand displacement reactions in RNA sequence design could contribute to sequential and spatiotemporal control of dynamic assembly, such as on-the-fly single-chain folding. Thanks to the development of data science and machine learning, data-driven and data-based strategies have started to show the power in RNA folding prediction as well as sequence generation for target structures. These computational tools offer an efficient means of exploring a sufficient number of RNA sequence-structure pairs to provide insights into what may work, thereby reducing the need for extensive wet-lab experimentation.

5 At the End

The Olympic motto, proposed in 1894, is the hendiatris Citius, Altius, Fortius, which means faster, higher, and stronger. The design, building, and assembly of DNA at nanoscales share a similar ethos with the Olympic games, striving for advancements in areas such as size, accuracy, versatility, adaptability and cost-effectiveness. Through DNA research, a single question can lead to many answers, and DNA assembly opens up endless possibilities for exploration. Nucleic acid nanostructures play the roles from nanomaterials to molecular devices and tools. As it continues to progress, it is only a matter of time before we  witness the widely adopted real-world applications of nucleic acid nanotechnology. The question now is which one will be the first.

Examples of exploiting DNA nanostructures as drug delivery vehicles have been demonstrated for targeted delivery with precise control of the structures, components, and reconfigurations [79,80,81,82,83]. Moreover, nucleic acid nanostructures have been investigated for other biomedical applications beyond drug delivery. For example, the cotranscriptionally folded single-stranded RNA origami showed significant anticoagulant activity which was sevenfold greater than free aptamer [84]. Researchers also developed a set of aptamer-decorated RNA origami with the ability to reverse the anticoagulation activity [85]. Single-stranded RNA origami has been used as an immunostimulatory reagent to stimulate innate response for cancer immunotherapy [86]. In a recent case, a half polyhedron shell formed from higher-ordered DNA origami assemblies works as a virus trap, which was decorated 90 sites of virus-binding moieties in its interior surface [87]. More innovative usages of nucleic acid nanostructures should be explored to fully benefit from their structural, dynamic, and functional features.

Individual 2D DNA origami has been placed onto lithographical patterns precisely for nanophotonic applications [88]. Arrays of DNA origami patterns with sizes larger than few micrometers can be integrated with top-down lithographic patterning techniques to access even larger length scales. One can imagine that the future 3D integration between DNA assemblies, such as 3D DNA superlattices, and top-down lithography could be implemented to address the needs of extending to the third dimension in nanofabrication.

The key to providing a vast library of described functionalities lies in creating hybrid systems that incorporate nucleic acid, proteins, lipid, quantum dots, and other functional materials. Adaptability issues are crucial for the successful creation of hybrid materials. With the consideration of efficacy, scalability, robustness, and safety, nucleic acid-directed assemblies and devices provide a multitude of possible applications that may produce novel materials with unique functionalities beyond our wildest imagination today.