Electrostatic Interactions‐Independent Approach for Efficient siRNA Encapsulation with Stimuli‐Responsive Charge Reversal and Controlled Release

Abstract Cationic materials currently serve as the primary materials for siRNA encapsulation; however, inherent cationic toxicity and limited shelf‐life have hindered their clinical applicability. Although several approaches for encapsulating siRNA without relying on cationic materials exist, achieving a high encapsulation efficiency remains a major challenge. In this study, a feasible strategy is developed for efficiently encapsulating siRNAs in nanogels, without the use of cationic materials. The use of amphiphilic monomers facilitated a higher concentration of monomers at the interlayer, presenting a superior polymerization capability in the inverse emulsion polymerization system. This facilitates the entrapment of siRNA within the nanogel rather than its extrusion. The pH‐responsiveness of the monomer and the enzyme sensitivity of the crosslinkers conferred several benefits to the siRNA‐loaded nanogels, including charge reversal, endo/lysosomal escape, and controlled siRNA release. The efficiency of the nanogel for siRNA delivery and gene inhibition is confirmed through a series of experiments. Thus, a feasible platform is developed for siRNA delivery that is free of cationic toxicity.