Nucleic Acid Nanostructures and their Cellular Transport Mechanisms

非技术性医疗应用中使用的分子和材料与我们的细胞和组织密切接触。这是真实的药物通常管理的病人，通过金属植入物用于重建手术。人造材料和自然生物系统之间的这些接触知之甚少，难以探测和优化。例如，药物可能会产生脱靶效应，植入物可能会导致不必要的排斥反应或疤痕。必须更好地理解和优化这些界面，以正确靶向组织，从而实现更好的治疗。该项目将开发新的策略，以了解材料如何与细胞相互作用。具体来说，就是要从根本上找到新的方法，将基于基因的治疗药物输送到患病组织。学生将面临医学，生物学，材料科学和化学方面的巨大挑战，同时专门研究适用于许多类型系统研究的先进聚合物和生化筛选技术。通过跨学科合作，该团队寻求广泛影响生物材料领域，但也强调了在通常明确定义的研究领域之外工作的积极成果，以在实验室中采用不同的方法来解决难题，以实现变革。TechnicalGianneschi及其同事开发了纳米颗粒，用于保护DNA免受酶降解，同时促进细胞进入，并能够调节活人类细胞中的mRNA水平，而没有明显的毒性。这一发展代表了朝着可以通过简单方案合成的无毒核酸递送系统的重大进步。然而，与许多其他生物活性纳米材料一样，细胞摄取、内体逃逸、mRNA调控和核酸酶抗性的机制尚不清楚。该项目的目标是开发一种普遍适用的方法，使研究人员能够了解细胞吸收纳米材料的机制。这也将有助于识别与纳米材料功能相关的潜在瓶颈，并促进下游应用材料的优化。通过先进的基因编辑工具和材料合成的结合，新的摄取途径将被发现，优化，然后用于调节基因表达，从而允许多种治疗疾病的途径，包括使细胞对它们原本抵抗的疗法敏感。拟议的工作是一个基本的生物材料研究的新结构，和新的生物界面。

Non-TechnicalMolecules and materials used in medical applications make intimate contact with our cells and tissues. This is true for pharmaceuticals commonly administered to patients, through to metal implants used in reconstructive surgery. These contacts between manmade materials and natural, biological systems are poorly understood, and difficult to probe and optimize. For example, medicines can have off-target effects, and implants can cause unwanted rejection or scarring. These interfaces must be better understood and optimized to correctly target tissues for better therapies. This project will develop new strategies for understanding how materials interact with cells. Specifically, to find fundamentally new methods for delivering gene based therapeutics to diseased tissues. Students will be exposed to a grand challenge in medicine, biology, materials science and chemistry, while working specifically on advanced polymers and biochemical screening techniques applicable to the study of many types of systems. Through interdisciplinary collaborations, the team seeks to impact both the field of biomaterials broadly, but also highlight the positive outcomes of working outside of normally well defined fields of study to bring different ways of approaching hard problems together in the lab to effect change. TechnicalGianneschi and coworkers have developed nanoparticles that serve to protect DNA from enzymatic degradation while facilitating cellular entry and are able to modulate mRNA levels in live human cells with no appreciable toxicity. This development represents a significant advancement towards non-toxic nucleic acid delivery systems that can be synthesized by simple protocols. However, as with many other biologically active nanomaterials, the mechanisms underlying, cellular uptake, endosome escape, mRNA regulation and nuclease resistance are not understood. This project's goal is to develop a universally applicable method that will allow researchers to understand the mechanisms involved in nanomaterial uptake by cells. This will also enable identification of potential bottlenecks that are associated with nanomaterial function and facilitate optimization of materials for downstream applications. Through a combination of advanced gene-editing tools and materials synthesis, new uptake pathways will be discovered, optimized, and then utilized to modulate gene expression allowing several routes towards treatment of disease including the sensitization of cells to therapies to which they are otherwise resistant. The proposed work is a fundamental biomaterials investigation of new structures, and new biological interfaces.