Trienzyme-like activities nanoreactor boosts tumor ferroptosis and mild photothermal therapy via gas/starvation synergy.

Mild photothermal therapy (mPTT) is often hindered by the upregulation of heat shock proteins (HSPs). To address this limitation, we designed a trienzyme-mimicking nanoreactor (MPGH) by functionalizing MnCO-loaded polydopamine (PDA) nanospheres with glucose oxidase (GOx)-doped hyaluronic acid. MPGH integrates the catalytic activities of GOx, peroxidase (POD), and glutathione peroxidase (GPX). Specifically, GOx consumes glucose to induce starvation therapy while simultaneously generating HO. The produced HO promotes MnCO decomposition, releasing CO for gas therapy and Mn to trigger mitochondrial dysfunction and reactive oxygen species (ROS) generation, thereby exhibiting POD-like activity. Meanwhile, the GPX-like activity of PDA depletes intracellular glutathione (GSH), downregulating glutathione peroxidase 4 (GPX4) to enhance ferroptosis. Importantly, both CO-mediated gas therapy and GOx-mediated starvation therapy disrupt cellular energy metabolism, reducing adenosine triphosphate (ATP) levels and suppressing HSP expression, which markedly enhances the efficacy of mPTT. This synergistic strategy of disrupting energy homeostasis demonstrated potent therapeutic outcomes against breast cancer.