A Tumor-Targeted Cascade Catalytic Nanoreactor for Microenvironment Remodeling and Photodynamic Immunotherapy

Hypoxia, glutathione (GSH) overexpression, and lactate accumulation within the solid tumor microenvironment severely constrain the efficacy of photocatalytic therapy. Here, we report a CD44-targeted cascade nanoplatform (CNMLH) constructed via layer-by-layer assembly to remodel this metabolic barrier. The platform features a hollow graphitic carbon nitride (CN) core, sequentially coated with an in situ grown MnO₂ shell, an electrostatically adsorbed lactate oxidase (LOx) layer, and an outermost hyaluronic acid (HA) coating. Upon HA-mediated internalization, the outer coating degrades to release LOx, which selectively consumes lactate to produce H₂O₂. Subsequently, the exposed MnO₂ shell scavenges endogenous GSH and converts the generated H₂O₂ into O₂. This catalytic cascade effectively disrupts the tumor's antioxidant defense system and alleviates local hypoxia. Consequently, under subsequent light irradiation, the CN core overcomes the hypoxic restriction to efficiently generate reactive oxygen species (ROS), thereby triggering robust immunogenic cell death (ICD). Both in vitro and in vivo experimental results confirm that this metabolism-intervening strategy effectively reverses the immunosuppressive microenvironment while eliciting antitumor immune responses.