Our research vision is to harness nucleic acid nanotechnology as a foundation for building intelligent molecular systems that can Structure, Sense, Actuate, and Compute—the fundamental capabilities of adaptive, programmable systems. By engineering DNA and RNA at the nanoscale, we aim to create a new class of materials and devices capable of dynamic decision-making and functional responsiveness. These systems will serve as the building blocks for programmable materials—materials that autonomously adapt to their environment—and programmable medicine, where therapeutic interventions are precisely regulated by molecular context, enabling personalized, real-time biomedical solutions.
This vision is rooted in four interconnected research pillars that define our lab’s foundational contributions to the field: Design, Assembly, Functionalization, and Interface. Together, these pillars have enabled the creation of sophisticated, biomimetic architectures with translational potential in both the life sciences and engineering.
Vision of the Yan lab research program.
Our design strategies aim to encode architectural and functional instructions directly into DNA sequences by making use of the predictability of Watson-Crick base pairing and the structural versatility of branched junctions and sequence-specific interactions. Over the past two decades, we have had the opportunity to contribute to the development of foundational principles for constructing programmable DNA nanostructures, helping advance the broader field of structural DNA nanotechnology.
Starting with the design of simple DNA tiles and lattices (Science, 2003, 301, 1882–1884), our early work demonstrated that DNA could serve as a molecular scaffold for organizing matter in periodic arrays. We have developed several frameworks for the development of DNA-based 3D crystals and lattices (J. Am. Chem. Soc. 2016, 138, 31, 10047–10054; Angew Chem Int Ed. 2018, 57, 12504–12507). By encoding connectivity and junction geometry directly into the structural design, we engineered crystalline assemblies with predictable architectures and tunable properties (J. Am. Chem. Soc. 2017, 139, 32, 11254–11260; J. Am. Chem. Soc. 2023, 145, 25, 13858–13868). We also demonstrated the precise spatial arrangement and atomic level structural characterization of DNA-binding molecules within rationally designed self-assembling DNA crystals, paving the way for using DNA lattices as scaffolds to study small molecules, peptides, and potentially proteins of unknown structure (J. Am. Chem. Soc. 2023, 145, 48, 26075–26085).
Building on the foundational principles of DNA self-assembly, we have contributed to the development of strategies for complex DNA and RNA origami designs. We introduced several methods for folding long scaffold strands into intricate 2D and 3D shapes using short staple strands (Science, 2011, 332, 342–346; Science, 2013, 339, 1412–1415; Nature Nanotechnology, 2015, 10, 779–784; Science, 2017, 358, 1402–1411). This design approach helped expand the structural and functional possibilities in the field, supporting the creation of more sophisticated nanostructures and enabling their potential use in areas such as dynamic molecular devices and programmable biomedical platforms.
Recognizing the growing complexity of these systems, we collaborated with computer scientists and engineers (Wonka, Bathe, Reif et al) to develop intuitive, robust design tools that integrate sequence design, structure visualization, and assembly prediction (Lecture Notes in Computer Science, 2008, 5347, 90–101). Our experimental work inspired the creation of automated software platforms capable of designing novel DNA nanostructures with minimal user input, further accelerating innovation across the field (Science, 2016, 352, 1534–1542; Science Advances, 2019, 5, eaav0655; Science Advances, 2022, 8, eade4455). These tools have empowered a broader community of researchers to engineer DNA-based devices with new capabilities, including reconfigurable architectures, algorithmic pattern formation, and molecular computation.
Together, these efforts have established a comprehensive design ecosystem—from fundamental tile-based assemblies to sophisticated DNA origami and crystalline lattices—underpinned by a fusion of molecular engineering and computational design. This approach has helped advance our ability to control matter at the nanoscale and holds promise for enabling future applications in areas such as nanotechnology, computation, and biomedicine.
We investigate the formation and evolution of nucleic acid nanostructures across space and time, gaining insight into the thermodynamics and kinetics that govern self-assembly. These studies inform the rational design of scalable, hierarchical, and responsive architectures capable of spatio-temporal control, algorithmic growth, and environmentally triggered behavior—mimicking the principles of natural development and morphogenesis.
Our investigations into the thermodynamics and kinetics of DNA self-assembly—often conducted in close collaboration with Yan Liu at ASU—have contributed to a deeper understanding of how to control the formation of complex DNA architectures, such as DNA origami tessellations (J. Am. Chem. Soc. 2014, 136, 3724–3727; ACS Nano 2017, 11, 9, 9370–9381; ACS Nano 2021, 15, 3, 5384–5396). By characterizing nucleation rates, growth dynamics, and energy landscapes at the molecular level, we have sought to identify key factors influencing assembly fidelity and yield. For example, through AFM imaging and kinetic modeling, we examined how the interplay between nucleation and growth affects the morphology and periodicity of DNA arrays. This mechanistic insight has helped guide the design of sequence-specific interaction rules and structural motifs that support predictable lattice formation.
In parallel, we have explored the sequence-dependent behavior of DNA Holliday junctions and their role in crystal assembly (Nature Communications, 2022, 13, 3112). Our crystallographic and molecular dynamics studies suggested that subtle sequence variations can influence junction flexibility, ion-binding properties, and, ultimately, crystal symmetry and resolution.
Taken together, these studies aim to bridge molecular-level insights with emergent material behavior, contributing to the broader effort of advancing nucleic acid nanotechnology toward adaptive, programmable systems that reflect the complexity and precision of natural self-assembly.
Examples of our fundamental studies of the DNA nanostructure self-assembly kinetics and junction sequence influenced crystallization processes (left: ACS Nano 2021, 15, 3, 5384–5396; right: Nature Communications, 2022, 13, 3112).
Another important focus of our research has been exploring the use of DNA nanostructures as chemically addressable scaffolds for organizing functional molecular and nanoscale components. By leveraging the programmability and nanoscale precision of DNA self-assembly, our group has contributed to the development of multifunctional nanostructures with capabilities in sensing, actuation, signal processing, and energy transduction.
We began by demonstrating the site-specific organization of inorganic nanoparticles on DNA scaffolds, helping to lay the groundwork for DNA-templated materials synthesis. In some of the early examples of this approach, we directed the placement of gold nanoparticles and quantum dots onto DNA templates with nanometer-scale precision (Nano Lett. 2006, 6, 248–251; Angew. Chem. Int. Ed. 2008, 47, 5157–5159; Science 2009, 323, 112-116; J. Am. Chem. Soc. 2011, 133, 17606–17609), establishing a methodology for constructing hybrid nanomaterials with potential applications in plasmonics, nanoelectronics, and catalysis. Alongside this, we developed strategies to synthesize nanomaterials suitable for chemical conjugation to DNA molecules (Angew. Chem. Int. Ed. 2008, 47, 316–319; J. Am. Chem. Soc. 2009, 131, 17744–17745; J. Am. Chem. Soc. 2012, 134, 17424–17427), enabling the DNA-directed self-assembly of nanoparticle architectures.
In parallel, through collaborations with Woodbury, Bathe, Liu, and others, we investigated DNA-templated light-harvesting and excitonic energy transfer systems inspired by natural photosynthetic complexes. By positioning covalently attached chromophores on DNA scaffolds, we were able to construct energy transfer cascades that emulate the spatial and directional control of biological systems (J. Am. Chem. Soc. 2011, 133, 11985–11993; J. Am. Chem. Soc. 2014, 136, 4599–4604; J. Am. Chem. Soc. 2014, 136, 16618–16625). These efforts facilitated the study of energy migration with high spatial resolution. Our later work demonstrated tunable excitonic coupling in dye aggregates and long-range energy transfer on DNA templates (Nature Materials 2018, 17, 159–166; J. Am. Chem. Soc. 2019, 141, 8473–8481; Chem 2022, 8, 2442–2459), offering new possibilities in quantum photonics and nanophotonic circuitry.
We also extended DNA nanostructure functionalization to study biomolecular interactions. For example, we developed multivalent ligand displays to probe spatial effects in ligand–receptor interactions (Nature Nanotechnology 2008, 3, 418–422), and later organized enzyme cascades on DNA frameworks to facilitate substrate channeling, enhancing catalytic efficiency through spatial confinement (J. Am. Chem. Soc. 2012, 134, 5516–5519; Nature Nanotechnology 2014, 9, 531–536).
Together, these efforts have contributed to the development of hybrid nanosystems that integrate inorganic, photonic, and biological components with a high degree of spatial precision. This line of research aims to bridge multiple disciplines and support emerging applications in synthetic biology, materials science, and molecular computing.
Examples of our DNA nanostructure directed assembly of metallic and semiconductor nanoparticles (left: Science 2009, 323, 112-116; J. Am. Chem. Soc. 2012, 134, 17424–17427), enzyme cascade (Nature Nanotechnology 2014, 9, 531–536) and light harvesting systems (Chem 2022, 8, 2442–2459).
While our lab has worked to develop a versatile set of tools for interfacing DNA nanostructures with inorganic materials—enabling controlled studies of physical phenomena such as plasmonic coupling and chiral metamaterial behavior—We believe that some of the most promising and potentially transformative applications of nucleic acid nanotechnology may emerge through its integration with biological systems. By drawing inspiration from the molecular language and components of life, we aim to design systems that can, in turn, contribute functional capabilities back to biology in a controlled and purposeful way.
Motivated by this perspective, we have developed nucleic acid-based platforms that interface with both natural and synthetic cell environments. By taking advantage of the structural programmability, biocompatibility, and sequence specificity of DNA and RNA, our work seeks to enable the incorporation of rationally designed nanostructures into living systems and engineered compartments with a high degree of control and functional versatility.
In the biomedical space, our research has contributed to establishing structural DNA nanotechnology as a foundation for smart therapeutic platforms. In collaboration with Ding and colleagues, we developed a DNA nanorobot designed for the targeted delivery of thrombin in response to tumor-associated markers—functioning autonomously to selectively induce tumor vessel thrombosis in vivo (Nature Biotechnology, 2018, 36, 258–264). Building on this work, we introduced CytoDirect, a nucleic acid-based nanodevice for cytoplasmic delivery of molecular payloads, which enables endosomal escape without the need for transfection agents (J. Am. Chem. Soc. 2023, 145, 27336–27347). This platform facilitates targeted delivery of RNAs and small molecules into the cytoplasm. In collaboration with Chang, we applied our RNA origami nanostructures (Science 2017, 358, eaao2648) as innovative platforms for cancer immunotherapy. Single stranded RNA origami demonstrated potent and safe immunostimulatory effects (ACS Nano 2020, 14, 4, 4727–4740) and serve as self-adjuvanted nanovaccines capable of eliciting robust anti-tumor immune responses (ACS Nano 2024, 18, 5, 4056–4067). More recently, we explored the use of DNA-templated scaffolds for organizing PROTAC (proteolysis targeting chimera) components, providing spatially defined control over protein degradation pathways and offering a modular approach to intracellular protein regulation (J. Am. Chem. Soc., 2025, 147, 29742-29755) (2025).
Another facet of our work involves integrating synthetic biology with nucleic acid nanotechnology. In earlier studies, we showed that rationally designed DNA assemblies could be replicated within living cells while retaining structural integrity (Proc. Natl. Acad. Sci. U.S.A., 2008, 105, 17626–17631). More recently, we engineered a reversibly gated DNA membrane channel capable of transporting proteins across lipid bilayers (Nature Communications 2022, 13, 2271). Inspired by native transporters, this synthetic system provides tunable control over transmembrane protein movement, contributing to efforts in synthetic cell development. In collaboration with Liu and colleagues, we also helped develop autonomously functioning DNA nanorobots that act as both gatekeepers and masseurs for synthetic cells—responding to environmental cues, interacting with lipid membranes, and carrying out localized mechanical and transport functions (Nature Material 2025, 24, 278–286). These devices represent examples of emergent behavior arising from engineered DNA assemblies.
Taken together, our work at the intersection of DNA nanotechnology and biology has aimed to support the development of a new class of programmable, responsive, and potentially evolvable nanosystems. These efforts are part of a broader movement to bridge biology, chemistry, and materials science, with the hope of contributing to future advances in therapeutic delivery, synthetic biology, and nanoscale engineering.
The above research directions aim to advance key capabilities that support the broader goal of developing adaptive molecular systems. By combining structural control with responsive functionality, our group seeks to contribute to the growing efforts toward next-generation molecular technologies. In doing so, we hope to help position nucleic acid nanotechnology as a valuable tool in the development of programmable materials and medicine, realizing a broader vision of advancing molecular design, translational science, and interdisciplinary discovery.
Looking ahead, the immediate future of our research program will focus on developing technologies and frameworks that push the boundaries of biomolecular science and molecular nanotechnology. Our efforts will center on the following key areas:
Atomic Precision and Scalable Synthesis of custom-designed biomolecular structures and assemblies, enabling new classes of functional architectures with unprecedented control at the nanoscale.
Universal Biomolecular Design Platforms, leveraging AI-driven strategies to engineer highly complex, multi-functional biomolecular systems with precision and adaptability across diverse applications.
On-Demand Biologics—such as siRNA, mRNA, and PROTACs—that are activated by endogenous cellular signals, opening new frontiers in programmable, adaptive medicine.
Precision Diagnostics, including the development of designer molecular probes for intraoperative pathology and live single-cell analysis, bringing molecular-level insight directly into clinical workflows.
DNA/RNA-Based Robotics and Non-Equilibrium Nanosystems, capable of performing tasks such as sensing, decision-making, and actuation within complex biological environments.
Integration with Quantum Materials and Information Science, bridging biomolecular assembly with next-generation quantum technologies to explore novel hybrid systems and computational paradigms.