Dual-responsive zwitterionic nanogels with synergistic charge reversal and hypoxia-activated drug release for precise tumor targeting and enhanced chemotherapy.

Developing nanomedicine delivery systems that respond to endogenous stimuli from the tumor microenvironment for the precise tumor targeting and controlled release of chemotherapeutic drugs has become a promising candidate to enhance cancer therapy. Here, we designed a zwitterionic nanogel system (named PMm) with charge-switchable and hypoxia-responsive properties for tumor targeting and on-demand drug release. PMm was synthesized through precipitation polymerization, strategically integrating a sulfamide-quaternary ammonium zwitterionic monomer (MPTA) and an azobenzene (azo) based crosslinker (MEFA). In the weakly acidic tumor microenvironment, PMm@DOX nanogels underwent a rapid surface charge reversal (to positive) via protonation of imine moieties, promoting deep tumor penetration and cellular uptake. Following cellular internalization, hypoxia-activated cleavage of the MEFA crosslinker induced the nanogel disassembly and DOX release, leading to the apoptosis of tumor cells. In vitro and in vivo studies demonstrated this dual-responsive nanogel platform synergistically integrated charge-driven targeting and hypoxia-triggered drug release, overcoming the limitations of conventional nanocarriers, enhancing tumor accumulation and showing superior antitumor efficacy. By intelligent surface engineering and microenvironmental responsiveness, the PMm@DOX system represents a promising strategy to amplify chemotherapeutic efficacy while minimizing off-target toxicity.