Charge-Mixing in Cationic Nanogels: A Dual-Way Regulation for Overcoming the Efficiency-Toxicity Delivery Dilemma

Cationic polymers, while widely used for therapeutic delivery of biomacromolecules, are constrained by a fundamental trade-off between efficacy and cytotoxicity. We report a mixed anionic-cationic nanogel platform that overcomes this limitation through cooperative regulation of charge and structure. By copolymerizing cationic and anionic monomers at programmed ratios, we precisely tune the net positive charge, substantially reducing toxicity without compromising delivery efficiency. The cross-linked network of the nanogel provides a stable yet open architecture, enabling siRNA loading both on interior and surface sites. When a nanogel particle is loaded with siRNA, deposition of serum proteins occurs largely on its surface, thereby both preserving the integrity of the encapsulated siRNA and maintaining the colloidal stability of the delivery vehicle. To ensure intracellular release of RNA, we incorporate redox-responsive cross-linkers that trigger nanogel disassembly in the reducing cytosolic environment. This dual charge-and-structure engineering strategy enables effective siRNA delivery with minimized adverse effects, and can be generalized to other charge-mixed systems and macromolecular cargoes. Our work thus provides a versatile solution to a long-standing challenge in cationic vector design, with broad implications for therapeutic nucleic acid delivery.