Enzyme-powered micellar nanoreactors enable tumor-specific, cascade-amplified prodrug activation for synergistic oxidation-chemo-immunotherapy.

Prodrug cancer nanomedicines have emerged as promising strategies to enhance drug solubility, reduce systemic toxicity, and improve tumor accumulation. However, the therapeutic efficacy of prodrug systems remains limited by suboptimal in vivo activation, resulting in non-functional accumulation at disease sites. Herein, we report the design of enzyme-powered, ultra-pH-sensitive micellar nanoreactors that orchestrate a tumor-specific, cascade-amplified prodrug activation mechanism for synergistic oxidation-chemo-immunotherapy. By encapsulating glucose oxidase (GOD) within paclitaxel-conjugated polymeric micelles, the nanoreactors exploit the acidic tumor microenvironment to initiate localized oxidative bursts, which not only amplify reactive oxygen species (ROS) generation but also accelerate pro-paclitaxel cleavage to release active paclitaxel in situ. The piperidine-functionalized nanoreactor architecture exhibits a tumor-acidity-triggered spatial rearrangement that alleviates steric hindrance, thereby enhancing enzymatic accessibility and catalysis while maintaining structural integrity. In vitro studies reveal potent cytotoxicity and immunogenic cell death (ICD) induction under acidic conditions, while in vivo experiments demonstrate efficient tumor-specific prodrug activation, oxidative microenvironment remodeling, and enhanced tumor accumulation. Notably, combining pro-paclitaxel nanoreactors with anti-PD-1 immune checkpoint blockade achieves robust tumor regression and significant survival extension in an orthotopic pancreatic cancer model. This study highlights the therapeutic potential of nanoreactor-driven cascade-amplified prodrug activation as a straightforward strategy to overcome pharmacological and immunological barriers in pancreatic cancer treatment.