Precise Assembly of Synthetic Carriers of siRNA through a Series of Interlocked Thermodynamically Self-Regulated Processes

A synthetic carrier of small interfering RNA (siRNA) with customizable size, pH-responsive degradability and optimized surface population of cell-targeting agents is constructed precisely through a series of interlocked thermodynamically self-regulated processes. This system consists of a unimolecular polyplex core formed from each individual molecule of networked cationic polymer and a multi-functional shell assembled from a rationally designed triblock copolymer. The core-forming polymer of defined size is synthesized via Zeta potential-regulated condensation of branched and linear multi-amine bearing oligomers through pH-responding imidazole conjugated imine linkages. The shell-forming copolymer consists of a multi-carboxyl saccharide end block to guide to the surface assembly, a hydrophobic central block to form an encapsulating layer, and a poly(ethylene glycol) end block equipped with a highly selective active ester for “hooking” various cell-targeting agents. Animal assays confirm the flexibility and convenience of this system to equip with selected functional components for systemic delivery of siRNA.