Nucleic Acid Nanostructures and their Cellular Transport Mechanisms

在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。对于通常给病人使用的药物，以及重建手术中使用的金属植入物，都是如此。人造材料和自然、生物系统之间的这些联系很少被理解，而且很难探测和优化。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或疤痕。这些界面必须更好地理解和优化，以正确地靶向组织，以获得更好的治疗。这个项目将开发新的策略来理解材料如何与细胞相互作用。具体来说，就是找到一种全新的方法，将基于基因的治疗方法输送到患病组织。学生将接触到医学，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，同时也强调在通常定义良好的研究领域之外工作的积极成果，将实验室中解决难题的不同方法结合在一起，以实现变革。技术上，gianneschi和他的同事已经开发出纳米颗粒，可以保护DNA免受酶降解，同时促进细胞进入，并且能够在没有明显毒性的情况下调节活细胞中的mRNA水平。这一发展代表了一个重大的进步，朝着无毒的核酸输送系统，可以通过简单的方案合成。然而，与许多其他生物活性纳米材料一样，细胞摄取、核内体逃逸、mRNA调控和核酸酶抗性的潜在机制尚不清楚。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。通过结合先进的基因编辑工具和材料合成，新的摄取途径将被发现、优化，然后用于调节基因表达，从而实现几种治疗疾病的途径，包括使细胞对原本具有抗性的疗法变得敏感。提出的工作是对新结构和新生物界面的基础生物材料研究。

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.