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

3D打印已经彻底改变了使用简单的计算机辅助设计（CAD）文件作为输入在宏观尺度上制造复杂固体物体的能力。在这个过程中，用户使用简单的几何图元或基于表面的网格来指定实体对象。这项革命性技术的最新应用包括打印假肢和植入物以及组织工程支架，以及从服装和眼镜到汽车，航空航天，自动化制造的类似转变始于20世纪70年代，使用CAD来设计使用超大规模集成电路（VLSI）的复杂电子产品。设计由数千个晶体管组成的电路。这场CAD革命还极大地增加和扩大了设计人员的参与，他们没有详细的技术知识来设计和合成定制电路，用于从移动的设备到生物医学植入物等行业的各种应用。在纳米尺度上，合成DNA的程序化自组装提供了类似的能力，可以“打印”具有精确定义的3D结构特征的复杂3D纳米尺度物体。虽然结构DNA纳米技术领域比前面的例子要年轻得多，但最近的技术和科学进步已经实现了低成本和可重复地合成不同结构的DNA纳米物体，实现了许多技术创新，包括铸造用于光子学和光捕获装置的金属纳米颗粒，制造模拟病毒用于药物和基因递送的治疗载体，以及开发用于疾病诊断中的生物标志物检测的纳米级传感器。结构DNA纳米技术目前面临着一个类似的瓶颈，在设计师的广泛参与，由于需要自动CAD为基础的设计软件，这些纳米物体。在这里，提出了下一代CAD框架的发展，使结构化DNA组装在纳米尺度上的全自动设计。作为一个出发点，CAD程序的开发在这里提出了一个独特的类的DNA为基础的对象称为DNA纳米笼的合成。DNA纳米笼可以被编程为在这个尺度上采用几乎任意的对称性和大小。此外，这些基于DNA的颗粒可以用蛋白质、RNA、发色团和其他小分子化学官能化，用于生物分子科学和技术中的各种应用。此外，这些纳米级材料可以转化为结构化的无机材料，包括金属和二氧化硅。为了实现改变设计和制造基于DNA的纳米材料的能力的目标，将开发一个开源软件包，使用简单的高级语言和CAD环境，通过万维网在全球范围内分发，从上到下规定纳米笼的尺寸和对称性。自组装形成这些CAD指定结构的合成DNA序列将自动生成用于纳米笼制造。纳米笼合成的验证将使用高分辨率结构和折叠分析进行实验。这项工作形成了一种新的高级编程语言的起点，该语言使用合成DNA在纳米级打印3D物体，这将广泛地使这些组件能够在各种研究和工业应用中使用和应用。未来的工作可能会将这一框架扩展到任意的2D和3D DNA组装，以及分子功能化的DNA组装，模仿，以及远远超出，自然的进化设计。

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.