Cascade Amplification of Photoimmunotherapy via Mitochondrial Dual-Ion Interference in a Bimetallic-Organic Framework

Mitochondria-targeted photodynamic immunotherapy has emerged as a promising strategy that combines organelle-specific delivery with immunomodulation for cancer treatment. However, inadequate photosensitizer efficiency and insufficient targeting often limit its therapeutic efficacy. To systematically address these limitations, we developed a ZIF-90-based immunomodulatory prodrug exhibiting mitochondria-associated accumulation that enables tumor therapy by synergistically integrating metal ion interference with in situ photoimmunotherapy. This prodrug undergoes disassembly in the high-ATP tumor microenvironment, releasing metal ions (Zn²⁺, Mn²⁺), and 5-aminolevulinic acid (5-ALA). 5-ALA is metabolized via the heme biosynthesis pathway to generate photoactive protoporphyrin IX (PpIX) within mitochondria. A detailed molecular docking and mechanistic study reveals that Zn^{2 +} potently inhibits ferrochelatase (FECH) by displacing its native Fe^{2 +} cofactor, thereby blocking PpIX-to-heme conversion and enabling unprecedented photosensitizer retention at the target site. The co-released Zn²⁺/Mn²⁺ ions further disrupt mitochondrial complexes I/II, resulted in electron transport chain collapse and amplified oxidative stress. Concurrently, Mn^{2 +} release was associated with cGAS-STING-related immune signaling and enhanced antitumor immune responses. This work demonstrates mitochondrial ion interference as a therapeutic cascade to enhance photoimmunotherapy, overcoming the limitations of traditional photodynamic therapy and immunosuppressive tumor microenvironments.