Design of mitochondria-targeting nanocomposites for enhanced catalytic cascade in multimodal tumor therapy

MnO₂@PDA@COTPP-GOx nanocomposites (MPCTG NCs) were engineered to enhance catalytic cascade reactions for multimodal tumor therapy through the integration of near-infrared (NIR) light activation, tumor microenvironment (TME) responsiveness, and mitochondrial targeting. This study was designed to systematically evaluate their therapeutic efficacy and underlying mechanisms both in vitro and in vivo. The nanocomposites exhibited TME-responsive degradation, effectively depleting glutathione (GSH) and catalyzing the conversion of endogenous H₂O₂ into oxygen and cytotoxic hydroxyl radicals (•OH), thereby alleviating tumor hypoxia and enhancing chemodynamic therapy (CDT). Glucose consumption mediated by GOx induced starvation therapy, generating gluconic acid and additional H₂O₂ to sustain MnO₂-catalyzed reactions and establish a self-amplifying CDT cycle. Upon NIR irradiation, spatiotemporally controlled release of carbon monoxide (CO) was achieved via the mitochondria-targeted CO donor (COTPP). In vitro experiments demonstrated that MPCTG NCs at a concentration of 60 μg/mL, in combination with NIR irradiation, reduced tumor cell viability to 4 %. In vivo, under laser irradiation, MPCTG NCs achieved 95.4 % inhibition of tumor growth, with no detectable systemic toxicity observed. This multifunctional platform synergistically integrates cascaded catalytic reactions with mitochondria-targeted gas therapy, presenting a promising translational strategy for broad-spectrum antitumor applications.