Virus-like particles are perfectly monodisperse self-assemblies of protein-only subunits that are ideal for therapeutic delivery applications because both capsid surfaces and interiors can be stoichiometrically decorated with moieties for cell targeting and siRNA capture/release. We will exploit the newly discovered SplitCore strategy for the formation of HBV capsids using fragment complementation of the separately expressed N- and C-cores to provide a streamlined approach to attach four unique decorations (3 exterior, 1 interior) to each HBV monomer into a highly modular nanoplatform suitable for customizable delivery and siRNA 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.
Gene silencing therapy based on siRNAs offer unique promise for cancer treatment by providing highly potent and target-specific silencing of genes dysregulated during cancer progression. However, delivery of siRNA remains extremely challenging because of its negative charge and tendency to degrade rapidly under physiological conditions. Furthermore, the unusual genetic and phenotypic signatures in aggressive cancers pose additional barriers for siRNA nanomedicines, as the invasive behaviors in these cells typically originate from simultaneous alterations in multiple cell surface receptors and gene expression profiles. Accordingly, there is an unmet need for therapeutic strategies able to more accurately target these cells by recognition of their specific balance in surface receptor expression, with the subsequent triggered release of appropriate siRNA cocktails. Design of such approaches could provide significant improvements in therapeutic efficacy relevant to metastatic cancers and a variety of other diseases. In this proposal, our objective is to design highly tunable, multi-functional Hepatitis B Virus (HBV) capsids suitable for cell-specific siRNA delivery in inflammatory breast cancer (IBC) cells, a canonical aggressive cancer whose invasive behavior is defined by multifactorial changes in gene expression.