A biomimetic magnetic MOF-based nanoplatform for H2S-mediated thermal re-sensitization and immune reprogramming in multimodal hyperthermia therapy

Magnetic hyperthermia therapy (MHT) has emerged as a promising anti-cancer strategy due to its precise spatial controllability and immune-activating effects. However, tumor cells can rapidly develop thermotolerance through the upregulation of heat shock proteins (HSPs), activation of the NF-κB signaling pathway, and recruitment of immunosuppressive cells, etc. Herein, we design a tumor cell membrane coated H2S-releasing magnetic nanoplatform (CmMN@ADT) to overcome this resistance. This nanoplatform was synthesized by coordinating Fe3O4 nanoparticles with 1,3,5-benzenetricarboxylic acid (BTC) to form a magnetic metal organic framework (Fe3O4@MIL-100, MN), which was subsequently loaded with the H2S donor ADT-OH and coated with tumor cell membranes for homotypic targeting. Upon exposure to an alternating magnetic field (AMF), the Fe3O4@MIL-100 core enables localized hyperthermia, while acidic tumor microenvironment triggers ADT-OH release for sustained H2S generation. The released H2S enhances tumor cell sensitivity to hyperthermia by inhibiting NF-κB activation and downregulating HSP expression. Suprisingly, H2S can also augment the MN induced ferroptosis. In vitro and in vivo studies have demonstrated that CmMN@ADT effectively induces tumor ablation and elicits potent anti-tumor immune responses, ultimately achieving the inhibition of the growth of both primary and metastatic tumors. Collectively, this study presents a novel H2S driven magnetic MOF nanoplatform that achieves dual mode synergy between H2S Augmented MHT and ferroptosis, providing a mechanistically guided strategy to overcome tumor thermotolerance and achieve durable tumor suppression.