High-biocompatibility chitosan-based vectors for high-dose gene therapy in tumor suppression and wound healing.
basic_science · Level V
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- Record sourced from PubMed, PMID 42033989.
- Also identified by DOI 10.1016/j.biomaterials.2026.124237.
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Abstract
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.