RNA delivery by self-assembling phagocytic-competent protein crystals

通过自组装具有吞噬能力的蛋白质晶体进行 RNA 递送

• 批准号: 10067767
• 金额: $ 30.24万
• 依托单位: CELL GUIDANCE SYSTEMS LIMITED
• 依托单位国家: 英国
• 项目类别: Collaborative R&D
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10067767
• 关键词: RNA; delivery; self; assembling; phagocytic

The mechanism by which a drug travels following administration (e.g. by intravenous injection) to reach its molecular target is critical to efficacy. Innovations in drug delivery have been fundamental to many medical advances. Most recently, RNA drugs, including widely used vaccines against SARS-CoV-2, have entered the market. RNA drugs required novel mechanisms of drug delivery which overcame specific challenges: Whilst conventional drugs act outside cells or are small enough to permeate through to intracellular targets, RNA drugs are only effective inside cells, and their large size necessitates a specific delivery mechanism to carry them across the cell wall and into the cell cytosol where they act.Viruses and lipid nanoparticles (LNPs, resembling small hollow spheres of fat) are used to deliver currently approved RNA drugs. Viruses and LNPs envelop and protect the RNA from damage whilst outside the cell and are able to dock or fuse with the cell wall to make the final delivery of RNA. However, these technologies have significant shortcomings including production costs, batch consistency, storage stability, immunogenicity, lack-of-targeting, the efficiency of cell entry, and endosomal escape. Whilst improvements in these technologies are being made, a fresh approach may better address these challenges.Particles access cells through a variety of passive and active mechanisms. Phagocytosis is a process in which cells actively ingest particles (most efficiently in the 0.3 - 5 microns size range). This process is particularly efficient in professional mononuclear phagocytic (MP) cells. These immune cells present vaccine antigens, ingest debris and eliminate invading pathogens. They also migrate to diseased and injured tissue and are involved in a variety of processes, including the generation of vaccine immunity, autoimmune diseases, wound healing and cancer. Some MPs, such as the liver's Kupfer cells, are not of haemopoietic origin. MPs also harbour many important pathogens. RNA drugs that effectively target MPs have the potential to impact many devastating diseases.We have engineered microscopic protein crystal particles, called PODS crystals, that contain specific bioactive protein cargos. MPs ingest PODS crystals and secrete their cargo proteins intact. We have also shown that cargo proteins enter the cytosol - the area of the cell where RNA is active - suggesting the possibility to deliver RNA. Here, we plan to generate protein crystal particles to deliver RNA to MP cells. Once this has been demonstrated, we will test RNAs' ability to modify MP cells' behaviour across a range of biomedical applications.

药物在给药后行进（例如静脉注射）达到其分子靶标的机制对于疗效至关重要。药物交付的创新对许多医学进步至关重要。最近，RNA药物（包括针对SARS-COV-2的广泛使用的疫苗）进入了市场。 RNA药物需要新颖的药物输送机制，以克服特定的挑战：而常规药物在细胞外部起作用或足够小，可以渗透到细胞内靶标，而RNA药物只有在细胞内有效，它们的大尺寸必须具有特定的递送机制，可以将它们带入细胞壁，并在细胞壁上携带。用于提供当前批准的RNA药物。病毒和LNP包膜并保护RNA免受细胞外部的损伤，并能够与细胞壁停靠或融合以使RNA的最终输送。但是，这些技术具有重大的缺点，包括生产成本，一致性，存储稳定性，免疫原性，靶向缺乏，细胞进入效率和内体逃生。尽管正在改进这些技术，但新的方法可以更好地解决这些挑战。粒子通过各种被动和主动机制访问细胞。吞噬作用是细胞主动摄入颗粒（最有效地在0.3-5微米尺寸范围内）的过程。该过程在专业的单核吞噬（MP）细胞中特别有效。这些免疫细胞呈现疫苗抗原，摄取碎屑并消除入侵的病原体。他们还迁移到患病和受伤的组织中，并参与了各种过程，包括疫苗免疫，自身免疫性疾病，伤口愈合和癌症的产生。一些国会议员，例如肝脏的kupfer细胞，不是造血的。国会议员还拥有许多重要的病原体。有效靶向MP的RNA药物具有影响许多毁灭性疾病的潜力。我们已经设计了含有特定生物活性蛋白肉类的显微镜蛋白晶体颗粒，称为PODS晶体。 MP摄入豆荚晶体并分泌其货物蛋白完整。我们还表明，货物蛋白进入细胞质 - RNA活性的细胞区域 - 表明可以输送RNA的可能性。在这里，我们计划生成蛋白质晶体颗粒，以将RNA输送到MP细胞。一旦证明了这一点，我们将测试RNA在一系列生物医学应用中修改MP细胞行为的能力。