Synchronously Delivering Melittin and Evoking Ferroptosis via Tumor Microenvironment‐Triggered Self‐Destructive Metal–Organic Frameworks to Boost Cancer Immunotherapy

Abstract The primary goal of treating malignant tumors is to efficiently eliminate the primary tumor and prevent metastasis and recurrence. Unfortunately, the immunosuppressive tumor microenvironment (TME) is a significant obstacle to effective oncotherapy. Herein, a therapeutic strategy based on melittin (MLT) encapsulated in hyaluronic acid‐modified metal–organic frameworks (MOFs) is pioneered, focusing on the safe delivery and TME‐responsive release of MLT to reshaping the immunosuppressive TME and simultaneously activating the immune system to eradicate cancerous cells. Iron‐based MOFs respond to glutathione and pH, degrade within a moderately acidic TME, and achieve tumor‐specific release of MLT. Additionally, the iron‐mediated Fenton reaction produces reactive oxygen species that augment oxidative stress, ultimately leading to tumor‐specific ferroptosis, whereas MLT‐induced membrane disruption promotes immunogenic cell death to activate the immune system. In combination with the immune checkpoint inhibitor anti‐PD‐L1, this nanodrug elicits potent antitumor immune responses, facilitating the infiltration of effector T cells and enhancing systemic antitumor T cell immunity to suppress both primary and distant tumors. This study demonstrates the tremendous potential of nanoscale self‐destructive MOFs for the targeted transport and controlled release of MLT and reveals the promoting effect of combined MLT and ferroptosis delivery on cancer immunotherapy.