Porphyrin oriented bimetallic sonodynamic MOF for enhanced ferroptosis and cGAS-STING pathway mediated antitumor immunotherapy

Sonodynamic therapy (SDT) offers deep tissue penetration and noninvasive tumor treatment, yet its efficacy remains limited by inadequate reactive oxygen species (ROS) generation and an immunosuppressive tumor microenvironment (TME). In this work, we developed a porphyrin-based bimetallic nanoplatform by integrating Fe and Mn centers within a structurally ordered metal-organic framework (MOF), followed by surface modification with the tumor-homing peptide CRGDK to achieve active targeting. The rationally engineered Mn-Fe(TCPP) MOF exhibits a spatially confined configuration that minimizes π-π aggregation of porphyrins enhancing ROS production under ultrasound (US). Meanwhile, Fe3+ and Mn2+ are released in the mildly acidic TME. The Fe3+ catalyzes Fenton-like reactions to generate abundant •OH radicals, leading to glutathione (GSH) depletion, glutathione peroxidase-4 (GPX4) inhibition, and triggers ferroptosis. Simultaneously, Mn2+ and ROS inflict mitochondrial damage and cause cytosolic double-stranded DNA (dsDNA) leakage, thereby activating the cGAS-STING signaling pathway and amplifying type I interferon (IFN-I) responses. This dual immunometabolic modulation induces immunogenic cell death (ICD), promotes dendritic cells (DCs) maturation, and strengthens adaptive antitumor immunity. Overall, this study presents a concise strategy coupling ferroptosis induction with innate-immune activation through a porphyrinic bimetallic MOF, offering a promising direction for SDT-based immunotherapy against hard-to-treat tumors. A CRGDK-conjugated Mn–Fe porphyrinic MOF (MFMP) with ordered confinement is constructed to achieve active targeting of tumor tissues. The ordered confinement suppresses ACQ and markedly enhances ultrasound-triggered ROS generation. Synergistic ferroptosis–pyroptosis promotes cytosolic dsDNA leakage and robust activation of the cGAS–STING pathway. MFMP achieves potent suppression of primary tumors, distant lesions, and pulmonary metastasis in the 4T1 triple-negative breast cancer model.