A H-MnO₂ nanoplatform for tumor microenvironment remodeling and multimodal synergistic therapy in prostate cancer

The efficacy of chemotherapeutic drugs is inherently dose-dependent, and their clinical application is often limited by systemic toxicity and poor tumor selectivity. Manganese dioxide (MnO₂) nanomaterials have attracted considerable interest in nanomedicine due to their favorable biocompatibility, efficient cellular uptake, and capacity to remodel the tumor microenvironment (TME). Docetaxel (DTX) remains a first-line treatment for advanced prostate cancer; however, its considerable side effects restrict therapeutic outcomes. To enhance the efficacy of DTX while reducing its toxicity, we encapsulated DTX into hollow MnO₂ nanoparticles pre-loaded with the photosensitizer IR825, constructing a multifunctional nanoplatform designated H-MnO₂@IR825/DTX. This nanoplatform leverages the catalase-like activity of H-MnO₂ to catalyze the decomposition of tumor-overexpressed H₂O₂ into O₂, thereby alleviating hypoxia and providing an endogenous oxygen source for photodynamic therapy (PDT). Under near‑infrared (NIR) irradiation, H-MnO₂@IR825/DTX generates both localized hyperthermia for photothermal therapy (PTT) and a burst of reactive oxygen species (ROS), which synergizes with the controlled release of DTX to achieve multimodal antitumor treatment. Mechanistically, the ROS burst not only activates the mitochondrial apoptosis pathway but also triggers pyroptosis via the NLRP3/Caspase-1/Gasdermin D (GSDMD) signaling axis, as validated by both in vitro and in vivo experiments. Meanwhile, the decomposition of MnO₂ depletes glutathione (GSH) and generates Mn²⁺ for chemodynamic therapy (CDT), further amplifying oxidative stress. Collectively, H-MnO₂@IR825/DTX integrates TME remodeling with PTT, PDT, CDT, and chemotherapy, eliciting potent synergistic antitumor effects against prostate cancer through ROS-dependent apoptosis and pyroptosis, while exhibiting low toxicity to normal cells. This rationally designed nanoplatform represents a promising strategy for effective and safe prostate cancer therapy.