Symbiotic Self-Assembly Strategy toward Lipid-Encased Cross-Linked Polymer Nanoparticles for Efficient Gene Silencing

A novel "symbiotic self-assembly" strategy that integrates the advantages of biocompatible lipids with a structurally robust polymer to efficiently encapsulate and deliver siRNAs is reported. The assembly process is considered to be symbiotic because none of the assembling components are capable of self-assembly but can form well-defined nanostructures in the presence of others. The conditions of the self-assembly process are simple but have been chosen such that it offers the ability to arrive at a system that is noncationic for mitigating carrier-based cytotoxicity, efficiently encapsulate siRNA to minimize cargo loss, be effectively camouflaged to protect the siRNA from nuclease degradation, and efficiently escape the endosome to cause gene knockdown. The lipid-siRNA-polymer (L-siP) nanoassembly formation and its disassembly in the presence of an intracellular trigger have been extensively characterized experimentally and through computational modeling. The complexes have been evaluated for the delivery of four different siRNA molecules in six different cell lines, where an efficient gene knockdown is demonstrated. The reported generalized strategy has the potential to make an impact on the development of a safe and effective delivery agent for RNAi-mediated gene therapy that holds the promise of targeting several hard-to-cure diseases.