High-biocompatibility chitosan-based vectors for high-dose gene therapy in tumor suppression and wound healing

The clinical translation of nucleic acid delivery systems demands the development of vectors that are not only efficient but also amenable to scalable production and safe for high-dose administration. Herein, we report a quaternary ammonium chitosan derivative (QCS)​ synthesized via a straightforward and scalable​ one-step amine-epoxy ring-opening reaction. This modification enhanced QCS's water solubility, DNA condensation capability and proton buffering capacity, facilitating efficient endo/lysosome escape. The optimal QCS3 formulation achieved transfection efficiency comparable to polyethyleneimine (PEI) but with dramatically reduced cytotoxicity and exceptional hemocompatibility. This superior safety profile enabled high-dose intravenous gene delivery, a regime severely limited by the toxicity of standard cationic polymers like PEI. ​In tumor-bearing mice, QCS3-mediated delivery of high-dose p53 plasmid effectively suppressed tumor growth, outperforming PEI, which was constrained to low, sub-therapeutic doses. Furthermore, leveraging the same QCS3 platform without modification, delivery of a plasmid encoding growth factor in a rat skin-defect model accelerated wound healing through robust endogenous factor expression. This work highlights QCS as a safe, efficient, and multifunctional gene delivery platform​ with high clinical potential for diverse applications.