EAGER: Collaborative Research: Algorithmic design principles for programmed DNA nanocages

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3D printing has revolutionized the ability to fabricate complex solid objects at the macroscopic scale using simple Computer-Aided Design (CAD) files as input. In this process, the user specifies the solid object using simple geometric primitives or surface-based meshes. Recent applications of this revolutionary technology include printing limb prosthetics and implants and tissue engineering scaffolds, as well as rapid prototyping of products in industries ranging from apparel and eyeware to automotive, aerospace, and art. A similar transformation in automated fabrication began in the 1970s using CAD for the design of complex electronics using very large scale integration (VLSI) to design circuits consisting of thousands of transistors. This CAD revolution also dramatically increased and broadened the participation of designers without detailed technical know-how needed to design and synthesize custom electrical circuits for diverse applications in industries ranging from mobile devices to biomedical implants. At the nanometer-scale, programmed self-assembly of synthetic DNA offers a similar ability to "print" complex 3D nanometer-scale objects with precisely defined 3D structural features. While the field of structural DNA nanotechnology is considerably younger than the preceding examples, recent technological and scientific advances have enabled the low-cost and reproducible synthesis of diverse structured DNA nano-objects, enabling numerous technological innovations including casting metallic nanoparticles for photonics and light-harvesting devices, fabricating therapeutic vectors that mimic viruses for drug and gene delivery, and developing nanoscale sensors for biomarker detection in disease diagnosis. Structural DNA nanotechnology currently faces a similar bottleneck in the broad participation of designers due to the need for automated CAD-based design software for these nano-objects. Here, development of a next-generation CAD framework is proposed to enable the fully automated design of structured DNA assemblies at the nanometer scale. As a starting point, the development of a CAD program is proposed here for the synthesis of a unique class of DNA-based objects called DNA nanocages. DNA nanocages can be programmed to adopt nearly arbitrary symmetries and sizes on this scale. Further, these DNA-based particles may be functionalized chemically with proteins, RNAs, chromophores, and other small molecules for diverse applications in biomolecular science and technology. In addition, these nanoscale materials can be transformed into structured inorganic materials including metals and silicon dioxide. To realize the aim of transforming the ability to design and fabricate DNA-based nanomaterials, an open-source software package will be developed to prescribe geometrically from the top-down nanocage size and symmetry using a simple high-level language and CAD environment that is distributed worldwide through the world-wide web. Synthetic DNA sequences that self-assemble to form these CAD-specified structures will be automatically generated for nanocage fabrication. Validation of nanocage synthesis will be performed experimentally using high-resolution structural and folding assays. This work forms the starting point for a new high-level programming language to print 3D objects at the nanometer-scale using synthetic DNA that will broadly enable the use and application of these assemblies across diverse research and industrial applications. Future work may extend this framework to arbitrary 2D and 3D DNA-based assemblies, as well as molecularly functionalized DNA-assemblies that mimic, as well as extend far beyond, nature's evolutionary designs.