Nanodelivery Vectors Veiled in Natural Killer Cell Membranes: Enhancing Colorectal Cancer Therapy through Synergistic Starvation and Chemotherapy

The application of oxaliplatin (L-OHP) in colorectal cancer chemotherapy has attracted considerable attention. However, its toxic side effects have hindered its clinical use. This study aims to develop a nanoparticle-based drug delivery system using L-OHP as the therapeutic agent, designated as NGMP. NGMP is designed to possess targeting capability, pH responsiveness, and MR imaging functionality. The ultimated goal of this system is to achieve a synergistic effect in colorectal cancer treatment by combining starvation therapy, chemodynamic therapy, and chemotherapy. NGMP delivers Manganese dioxide (MnO₂) into tumor cells, where the acidic and glutathione (GSH)-rich tumor microenvironment (TME) rapidly triggers its degradation. This reaction liberates L-OHP, glucose oxidase (GOX), and Mn²⁺ ions. The released Mn²⁺ catalyzes a Fenton-like reaction with endogenous hydrogen peroxide (H₂O₂), producing abundant reactive oxygen species (ROS) and driving oxidative damage-induced cell death. Concurrent GSH depletion sensitizes tumor cells to ROS and chemotherapeutic agents, thereby amplifying cytotoxicity. GOX-mediated glucose consumption induces metabolic starvation (starvation therapy), simultaneously replenishes H₂O₂, and lowers the local pH, thereby establishing a positive feedback loop that synergistically enhances both starvation therapy and chemodynamic therapy. Collectively, these effects result in self-amplifying, multimodal tumor eradication. NGMP is cloaked with natural killer cell membranes (NKm) to enhance tumor specificity and modulate immune responses. This coating enables immune evasion, facilitates active tumor targeting, and promotes immunotherapeutic synergy. Compared with free L-OHP, NGMP demonstrates superior antitumor efficacy, greater biocompatibility, and integrated diagnostic functionality. These combined features position NGMP as a potential theranostic platform for colorectal cancer.