Redox-programmed AQ4N-based nanoreactor for hypoxia amplified bio-reductive chemotherapy with chemo-dynamic and photodynamic modulation.

Recognition that solid tumors reside within a profoundly hypoxic and oxidoreductase-rich microenvironment has positioned bioreductive prodrugs as a rational strategy for tumor-selective chemotherapy. Among them, the anthraquinone di-N-oxide AQ4N (banoxantrone) carries two hypoxia-sensitive tertiary amine N-oxide "switches" that are sequentially reduced in hypoxic tumor regions to yield the highly cationic DNA-intercalating topoisomerase II poison AQ4. However, its antitumor efficacy remains limited by insufficient tumor accumulation and heterogeneous hypoxia-driven activation. Here, we exploit PtO coordination to construct a carrier-free nanoreactor (APC) via co-assembly of AQ4N, a Pt[IV] prodrug, and chlorin e6 (Ce6). Under near-infrared irradiation, Ce6-mediated photodynamic oxygen consumption further aggravates local hypoxia, thereby promoting the hypoxia-dependent conversion of AQ4N to AQ4 and the bioreduction of Pt[IV] to Pt[II]. The generated Pt[II] catalyzes Fenton-like reactions with endogenous H2O2 to produce hydroxyl radicals, providing chemodynamic damage that cooperates with photodynamic oxidative stress to amplify AQ4 cytotoxicity. Overall, APC potentiates AQ4N-based bioreductive chemotherapy against hypoxic solid tumors, with chemodynamic and photodynamic effects serving as synergistic auxiliary modalities.