All-in-One Mitochondria-Targeted Iron-Based MOF “Nanomissiles” for Synergistically Potentiated Tumor Ferroptosis, Dual Phototherapy, and Chemotherapy

Pronounced heterogeneity and adaptability of tumors inherently curtail monotherapeutic efficacy, necessitating rationally integrated multimodal regimens that enable precise intervention, overcome resistance, and eradicate heterogeneous cell populations within the complex tumor microenvironment (TME). All-in-one mitochondria-targeted “nanomissiles” were created by emodin (Em)-Fe3+-gated, doxorubicin (DOX)-loaded PCN-600(FeIII) (denoted as DOX@ME) nanoparticles for synergistic multimodal tumor therapy integrating ferroptosis, photodynamic therapy (PDT), mild photothermal therapy (MPTT), and chemotherapy. DOX@ME achieved on-demand release of DOX in response to the TME [such as low pH, glutathione (GSH), hydrogen peroxide (H2O2), and adenosine-5′-triphosphate (ATP)] and near-infrared laser, via the disassembly of the Em-Fe3+ gating films and/or the degradation of the PCN-600(FeIII) nanocarriers. Under both 660 and 808 nm laser irradiation, DOX@ME effectively triggered apoptosis via chemotherapy, PDT, and MPTT while robustly accelerating reactive oxygen species (ROS) generation, GSH depletion, glutathione peroxidase 4 (GPX4) downregulation, and lipid peroxide (LPO) accumulation to enhance ferroptosis. Moreover, DOX@ME could alleviate thermotolerance by depleting intracellular ATP and downregulating protective heat shock protein 70 to boost the curative efficacy of MPTT. DOX@ME exhibited excellent antitumor efficacy and good biocompatibility and biosafety in A549 tumor-bearing nude mice. Collectively, DOX@ME demonstrates robust clinical translational potential for precision cancer therapy.