Biodegradable dual-responsive amino acid-based zwitterionic nanogels for enhanced cancer therapy

Zwitterionic polymers have emerged as a powerful platform for constructing stealth nanocarriers owing to their superior antifouling capability and excellent biocompatibility. Herein, we report a biodegradable zwitterionic nanogel, P(VCL-ss-OrnAA), featuring synergistic thermo-and redox-responsiveness, prepared via aqueous precipitation copolymerization of N-vinylcaprolactam (VCL), ornithine methacrylamide (OrnAA), and a disulfide-containing crosslinker. The incorporation of ornithine-derived zwitterionic moieties endows the nanogels with remarkable colloidal stability and pronounced resistance to nonspecific protein adsorption, conferring desirable stealth characteristics in biological environments. The nanogels exhibit a well-defined temperature-triggered swelling-to-collapse transition in aqueous media, together with efficient redox-responsive degradation mediated by disulfide linkages under reductive intracellular conditions. When loaded with doxorubicin (DOX), the nanogels display negligible premature leakage under physiological conditions, accelerated drug release at elevated temperatures, and rapid payload liberation in reductive environments, enabling spatiotemporally controlled drug delivery. In vitro studies demonstrate minimal cytotoxicity of blank nanogels toward both normal and cancer cells, while DOX-loaded P(VCL-ss-OrnAA) nanogels achieve significantly enhanced tumor cell growth inhibition compared with DOX-loaded PVCL counterparts. Furthermore, in a colorectal tumor-bearing mouse model, the nanogel formulation exhibits pronounced tumor suppression efficacy. Collectively, these results highlight P(VCL-ss-OrnAA) nanogels as a promising zwitterionic nanoplatform for precision cancer therapy.