Calcium/Manganese Nanoreactors Enable Triple-Enhanced Chemodynamic/Photodynamic Therapy via Tumor Microenvironment Reprogramming

While reactive oxygen species (ROS)-dependent chemodynamic therapy (CDT) and photodynamic therapy (PDT) hold promise for cancer treatment, their efficacy remains constrained by tumor microenvironment (TME) barriers: glutathione (GSH) overexpression, insufficient H2O2 supply, and hypoxia. To address these limitations, we engineered a Trojan horse-inspired MnO2-shelled CaO2 nanoreactor (CaO2/MnO2–Ce6-PEG) by employing a sequential TME reprogramming strategy, triggering a cascading ROS storm for enhanced CDT and PDT. The outer MnO2 layer first depletes GSH through redox conversion, exposing the CaO2 core hydrolysis, and subsequently providing H2O2 for CDT and O2 for ameliorating hypoxia to boost Ce6-mediated PDT. In vitro studies demonstrate that the nanoreactor enables efficient cellular internalization and intracellular GSH depletion with continuous H2O2/O2 generation, achieving synergistic CDT and PDT in malignant cells. In vivo studies show that the nanoreactor potently inhibits tumor growth in murine tumor models with negligible systemic toxicity, due to Trojan horse architecture enabling TME-responsive shell dissociation and spatiotemporally controlled payload release. The rationally designed nanoreactor enables triple-enhanced CDT/PDT via TME-reprogramming capabilities: GSH-mediated antioxidant defense blockade, ROS precursor replenishment, and hypoxia reversal. This work provides a self-reinforcing platform by dynamically reprogramming multiple TME barriers to ROS-based anticancer therapy.