Engineering Smart Protein Coronas to Advance Theraputic mRNA Delivery

设计智能蛋白冠以推进治疗性 mRNA 传递

• 批准号: 9911201
• 负责人: Jilian R Melamed
• 金额: $ 6.12万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911201
• 关键词: Engineering; Smart; Protein; Coronas; Advance; Engineering; Smart; Protein; Coronas; Advance

While gene therapy with mRNA offers tremendous potential to transform the management of genetic diseases, delivering mRNA outside the reticuloendothelial system (e.g. liver and spleen) remains challenging. Without carriers that can reach organs such as the lungs, heart, brain, or pancreas, the potential of mRNA to treat diseases of those organs, such as asthma, coronary artery disease, multiple sclerosis, and diabetes, will remain untapped. This research will establish the protein corona as a new lipid nanoparticle design element that can be engineered to achieve mRNA delivery outside the reticuloendothelial system. Upon injection into the body, lipid nanoparticles are immediately coated in local proteins, forming a protein corona that interfaces with cells and tissues. The composition of that natural corona has been shown to strongly influence nanoparticle fate in vivo. This work will develop “smart” protein coronas by pre-coating mRNA lipid nanoparticles with proteins that localize to organs outside the reticuloendothelial system prior to administration. In Aim 1, a small library of naturally-occurring proteins will be evaluated for their ability to direct mRNA delivery to non-reticuloendothelial organs, including the lungs, heart, brain, and pancreas, in C57BL/6 mice. Imaging and flow cytometry will be used to identify organ and cellular targets of smart corona-coated mRNA lipid nanoparticles. Aim 2 will elucidate the mechanisms by which smart corona-coated lipid nanoparticles enable differential organ targeting. Smart coronas may enable differential targeting by altering circulation time, by recruiting additional serum proteins that serve as active targeting agents, or by binding specific cell surface receptors via the smart corona itself or via additionally adsorbed proteins. Proteomic analysis will determine what proteins adsorb coated-lipid nanoparticles upon intravenous injection, and cell receptor blocking studies will identify cellular targets that facilitate effective mRNA delivery. This work is innovative in that it will establish the protein corona as a previously-unappreciated nanoparticle design element that can be engineered to enable mRNA delivery to challenging organ targets. While efficacious smart coronas will provide researchers with new tools to advance drug targeting, mechanistic insights will inform future smart corona design. This research is significant because it will contribute a paradigm-shifting targeting strategy to accelerate the clinical translation of mRNA therapeutics for extrahepatocellular diseases. Further, the results obtained by this research will advance the delivery of nucleic acids, small molecules, and proteins from diverse drug carriers, such nanoparticles, drug conjugates, and implantable devices. Ultimately, the knowledge generated by this work has the potential to transform and accelerate the development of targeted drug carriers.

虽然用mRNA的基因疗法具有巨大的潜力来改变通用的管理 疾病，在网状内皮系统（例如肝脏和脾脏）之外传递mRNA仍然受到挑战。 没有可以到达肺，心脏，大脑或胰腺等器官的载体，mRNA的潜力 治疗这些器官的疾病，例如哮喘，冠状动脉疾病，多发性硬化症和糖尿病 保持未开发。这项研究将确定蛋白质电晕作为一种新的脂质纳米颗粒设计元素 可以设计以在网状内皮系统之外实现mRNA递送。注入 身体，脂质纳米颗粒立即涂在局部蛋白质中，形成与链接的蛋白质电晕 细胞和组织。该天然电晕的组成已显示出强烈影响纳米颗粒的命运 体内。这项工作将通过用蛋白质预涂mRNA脂质纳米颗粒来发展“智能”蛋白冠 在给药之前，请定位在网状内皮系统之外的器官。 在AIM 1中，将评估一个天然蛋白质的小库，以指导mRNA的能力 在C57BL/6小鼠中递送至非肉毒节内皮器官，包括肺，心脏，大脑和胰腺。 成像和流式细胞仪将用于识别智能电晕涂层mRNA脂质的器官和细胞靶 纳米颗粒。 AIM 2将阐明智能电晕涂层脂质纳米颗粒启用的机制 差异器官靶向。智能冠状运动可以通过改变循环时间来实现差分定位 募集用作活性靶向剂或通过结合特定细胞表面的其他血清蛋白 通过智能电晕本身或通过吸附蛋白的受体。蛋白质组学分析将确定什么 蛋白质在静脉注射后吸附涂层的脂质纳米颗粒，细胞受体阻断研究将 确定促进有效mRNA递送的细胞靶标。 这项工作具有创新性，因为它将建立蛋白质电晕作为先前未接受的 纳米颗粒设计元件可以设计以使mRNA递送以挑战器官靶标。尽管 Easy Smart Coronas将为研究人员提供新的工具，以推动药物靶向，机械见解 将告知未来的智能电晕设计。这项研究很重要，因为它将贡献范式转移 靶向策略，以加速mRNA疗法的ePARHEPATOCOLULURALURALIC疾病。 此外，这项研究获得的结果将推动核酸，小分子和 来自潜水员药物携带者，此类纳米颗粒，药物缀合物和可植入装置的蛋白质。最终， 这项工作产生的知识有可能改变和加速目标的发展 毒品载体。