Development of the next generation of lipid nanoparticles for gene therapy

脂质纳米颗粒（LNPs）是药物递送、功能基因组学和生物技术和医学中其他应用的革命性工具。他们即将实现个性化医疗的梦想之一：癌症等疾病的个体基因治疗。对导致肿瘤生长的“流氓”基因的了解是相当多的，但要有效地关闭或“沉默”这些基因，仍然存在许多重大障碍。最有前途的基因治疗方法是利用短的双链RNA（siRNA），其序列允许它与癌症基因的信使RNA结合，之后天然细胞机制降解它。在细胞内递送后，siRNA已被证明具有体外沉默特定基因的能力。然而，体内使用siRNA需要复杂的递送技术，因为“裸”siRNA在循环中迅速分解，不在疾病部位积累，并且不能穿透靶细胞膜到达其细胞内作用部位。将siRNA包封在LNP中保护siRNA免于在血流中降解，并且使得siRNA能够经由胞吞作用内在化于细胞内。然而，在增加LNP的实际使用方面仍有大量工作要做。LNP siRNA系统的纳米结构和它们所含的五种不同脂质组分的功能作用尚未得到很好的理解，阻碍了开发下一代系统的努力，这些系统稳定，可靶向不同组织，易于制造，并符合监管要求。在这个项目中，我们将使用计算机建模和生物物理表征来研究不同组分在确定LNP的结构、大小、靶向特性和内体释放机制中的作用。我们将测试我们在设计和制造新LNP方面的知识。这将导致LNP的合理设计技术得到改进，这将大大扩展其作为抗癌药物和功能基因组学工具的用途，通过我们的合作伙伴Precision NanoSystems，这两种技术的商业化机会广泛，并开发针对特定形式癌症的药物。

Lipid nanoparticles (LNPs) are a revolutionary tool for drug delivery, functional genomics and other applications in biotechnology and medicine. They are on the verge of enabling one of the dream applications of personalized medicine: individual gene therapy in diseases such as cancer. Knowledge of the "rogue" genes responsible for tumour growth is substantial but there remains a number of significant obstacles to effectively turning these genes off or "silencing" them. The most promising gene therapy approach utilizes short pieces of double stranded RNA (siRNA) whose sequence allows it to bind to the cancer gene's messenger RNA, after which a natural cellular mechanism degrades it. Following intracellular delivery siRNAs have demonstrated abilities to silence specific genes in vitro. However, the use of siRNA in vivo requires sophisticated delivery technologies, since "naked" siRNAs are rapidly broken down in the circulation, do not accumulate at disease sites and cannot penetrate target cell membranes to reach their intracellular sites of action. Encapsulating siRNA in an LNP protects the siRNA from degradation in the bloodstream, and enables the internalization of the siRNA within the cell via endocytosis. However, considerable work remains to increase the practical use of LNPs. The nanostructure of the LNP siRNA systems and the functional roles of the five different lipid components they contain are not well understood, impeding efforts to develop next generation systems that are stable, can be targeted to different tissues, are straightforward to manufacture, and meet regulatory requirements. In this project, we will use computer modelling and biophysical characterization to investigate the role of the different components in determining the structure, size, targeting properties and the endosomal release mechanism of LNPs. We will test our knowledge in the design and manufacture of new LNPs. This will lead to improved rational design technology for LNPs that will greatly expand their use as anti-cancer drugs and functional genomics tools, with extensive opportunities for commercialization of both technology, through our partner Precision NanoSystems, and the development of drugs for specific forms of cancer.