A Biomimetic cascade nanoreactor enabled by tumor microenvironment remodeling for precise CO release and enhanced cu-mediated chemodynamic therapy

Prostate cancer (PCa) is the most prevalent malignant tumor in the male genitourinary system. Carbon monoxide (CO) gas therapy and chemodynamic therapy (CDT) have emerged as alternative treatments for cancer. However, the therapeutic efficacy of both approaches is constrained by the insufficient endogenous hydrogen peroxide (H 2 O 2 ) supply and the overexpression of protective glutathione (GSH) in the tumor microenvironment (TME). Herein, we developed a biomimetic cascaded nanoreactor (DCM@MCuH@MnCO) for synergistically combining CO-mediated gas therapy with CDT driven by depletion of GSH and self-supply of H 2 O 2 in the tumor. DCM@MCuH@MnCO was constructed by integrating a copper-catechol coordinated network (CuH) and H 2 O 2 -sensitive manganese carbonyl (MnCO) within the mesoporous carbon hollow spheres (MCHS), and further modifying the surface with tumor cell membranes (DCM) to enhance its tumor-targeting ability. The CuH in the nanoreactor can disassemble, triggered by continuous consumption of GSH, releasing pro-oxidative catechol ligands to generate H 2 O 2 for TME remodeling. Subsequently, MnCO decomposes on demand to release CO in situ while copper ions (Cu + ) convert H 2 O 2 into reactive oxygen species (ROS) via a Fenton-like reaction. These events cooperatively cause mitochondrial damage and induce a lethal ROS storm within cells, ultimately effectively killing tumor cells both in vitro and in vivo. This study demonstrates significant prospects for CO therapy and CDT, offering a novel and promising strategy for efficient PCa treatment. Graphical