Design of Multi-Functional SplitCore HBV Capsids for Precisely Controlled Multi-siRNA Delivery in Cancer Therapeutics

到2030年，全球可能有2700万癌症病例。基因沉默疗法通过在癌症进展期间提供高度有效和靶向特异性的基因沉默，为癌症治疗提供了独特的前景。使用基因沉默治疗癌症所面临的主要技术障碍是需要改善递送和保护其免受生理条件下的快速降解。为了解决这个问题，该计划将通过靶向肿瘤表面高度表达的受体来设计适合细胞特异性递送的多功能乙型肝炎病毒（HBV）衣壳。B病毒。HBV衣壳被设计为基于pH变化在细胞内释放基因沉默剂。在该项目上接受培训的学生将在预计将显著提高生物材料能力的研究背景下接受多学科培训。技术说明开发有效的siRNA载体在肿瘤治疗中具有重要意义。基于SplitCore HBV技术的病毒样颗粒（VLP）非常适合于此目的，它提供了一种变革性的方法，将四种独特的装饰（3种外部，1种内部）连接到每个HBV单体上，形成一个高度模块化的纳米平台，适合于定制的细胞靶向和siRNA捕获/释放。这一重大进展可以通过引入靶向配体以及siRNA的明确组合来实现细胞特异性和治疗功效的关键增加，最终产生将病毒的递送效率与非病毒载体的设计多功能性融合的杂交结构。 设计的简单性允许创建适用于一系列癌症靶点的高度适应性的多功能HBV衣壳。

Nontechnical descriptionBy 2030, there could be 27 million incident cases of cancer worldwide. Gene silencing therapies offer unique promise for cancer treatment by providing highly potent and target-specific silencing of genes during cancer progression. The major technological hurdles confronting the use of gene silencing for cancer treatment are the needs for improved delivery and protection from rapidly degradation under physiological conditions. To tackle this problem, this program will design multi-functional Hepatitis B Virus (HBV) capsids suitable for cell-specific delivery by targeting receptors that are highly expressed on the surface of tumors. HBV capsids are designed to release the gene silencing agents inside of cells based on pH changes. The students trained on this project will be exposed to multi-disciplinary training in the context of research that is anticipated to significantly advance biomaterials capabilities. Technical descriptionThe development of effective therapeutic vehicles for siRNA delivery is of essential importance in cancer treatment. Virus-like-particles (VLPs) based on the SplitCore HBV technology are ideally suited for this purpose by providing a transformative approach to attach four unique decorations (3 exterior, 1 interior) to each HBV monomer into a highly modular nanoplatform suitable for customizable cell targeting and siRNA capture/release. This significant advance can enable key increases in both cell specificity and therapeutic efficacy through incorporation of well-defined combinations of targeting ligands as well as siRNAs, ultimately creating hybrid structures that fuse the delivery efficiency of viruses to the design versatility of non-viral vehicles. The simplicity of the design allows the creation of highly adaptable, multi-functional HBV capsids suitable for a range of cancer targets.