H2O2- and light-triggered MnO2-based nanoswitches for microenvironment reprogramming and photodynamic therapy of hypoxic atherosclerotic plaques

M1 macrophage-enriched hypoxic microenvironment within high-risk plaques accelerates atherosclerosis progression. Notably, intraplaque hypoxia severely limits the therapeutic efficacy of oxygen-dependent photodynamic therapy (PDT). In this study, we report a rationally engineered oxygen-generating manganese dioxide (MnO 2 )-based nanoswitch system that integrates plaque microenvironmental reprogramming with enhanced, activatable PDT for the precise treatment of hypoxic atherosclerotic plaques. The HA-TEPA/MnO 2 /Ce6 nanoswitches are readily synthesized via sequential reactions of tetraethylenepentamine-modified hyaluronic acid (HA-TEPA), potassium permanganate, and chlorin e6 (Ce6)-NH 2 . Under physiological conditions, the MnO 2 effectively quenches both fluorescence and singlet oxygen generation of Ce6, maintaining the nanoswitch in a photodynamically “off” state to minimize off-target phototoxicity and skin photosensitization. Following CD44-mediated selective uptake by activated macrophages, endogenous hydrogen peroxide (H 2 O 2 )-triggered MnO 2 degradation induces H 2 O 2 -to-O 2 transition. This trigger-responsive transition alleviates local hypoxia to enhance the PDT efficacy and reprogram macrophages toward a pro-resolving, anti-inflammatory M2 phenotype. Concurrently, H 2 O 2 -triggered MnO 2 degradation restores the intrinsic Ce6 fluorescence and photodynamic activity, enabling activatable PDT in plaques under laser irradiation. In vivo evaluation using a hypoxic atherosclerotic plaque model demonstrates that photoactivated HA-TEPA/MnO 2 /Ce6 nanoswitches significantly promote pro-inflammatory macrophage depletion, reduce lipid core burden, and enrich collagen content, thereby driving robust plaque stabilization and regression without inducing systemic toxicity. Collectively, these findings establish this state-switchable therapeutic platform as a highly promising, stimulus-responsive nanomedicine strategy for environmentally activated atherosclerosis therapy.