Mitochondria-Targeted Zwitterionic Nanogels Trigger Photopyroptosis for Enhanced Cancer Therapy

Precise induction of pyroptosis remains a formidable challenge in cancer therapy due to the stringent requirements for spatiotemporal and subcellular control. Herein, we report a zwitterionic nanogels platform (poly(N-oxide dimethylaminoethyl methacrylate), PODMMA) that enables precise induction of photopyroptosis via intrinsic mitochondrial targeting. Owing to its unique N-oxide zwitterionic structure, the PODMMA nanogels exhibit prolonged blood circulation, selective mitochondrial localization without the need for additional targeting ligands, and enhanced tumor accumulation. In vitro studies demonstrate that the drug-loaded nanogels efficiently accumulate in mitochondria. Upon irradiation with a 640 nm laser (5 min, 30 mW/cm²), reactive oxygen species (ROS) amplification is triggered leading to the activation of the caspase-3/gasdermin E (GSDME) pyroptosis pathway. In vivo evaluations demonstrate exceptional therapeutic efficacy with 99.3% tumor inhibition and negligible systemic toxicity. This study establishes a versatile strategy for subcellular-targeted photopyroptosis and precision cancer therapy.