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

非技术描述到2030年，全球可能会有2700万癌症病例。基因沉默疗法通过在癌症进展过程中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。利用基因沉默治疗癌症面临的主要技术障碍是需要改进递送和防止在生理条件下迅速降解。为了解决这个问题，这个项目将设计适合细胞特异性递送的多功能乙肝病毒衣壳，通过靶向肿瘤表面高表达的受体。根据pH值的变化，乙肝病毒衣壳被设计成在细胞内释放基因沉默剂。在这个项目上接受培训的学生将在预期将显著提高生物材料能力的研究背景下接受多学科培训。技术描述开发有效的siRNA治疗载体在癌症治疗中至关重要。基于SplitCore乙肝病毒技术的病毒样颗粒(VLP)非常适合这一目的，它提供了一种变革性的方法，将四个独特的装饰(3个外部，1个内部)连接到每个乙肝病毒单体上，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明确定义的靶向配体和siRNA的组合来关键地提高细胞特异性和治疗效果，最终创造出融合病毒递送效率和非病毒载体设计多功能性的杂交结构。设计的简单性允许创建高度适应性、多功能的乙肝病毒衣壳，适用于一系列癌症靶点。

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.