Metal‐Organic Layer Delivers 5‐Aminolevulinic Acid and Porphyrin for Dual‐Organelle‐Targeted Photodynamic Therapy

The efficacy of photodynamic therapy (PDT) depends on the subcellular localization of photosensitizers. Herein, we report a dual‐organelle‐targeted nanoparticle platform for enhanced PDT of cancer. By grafting 5‐aminolevulinic acid (ALA) to a Hf12‐based nanoscale metal‐organic layer (Hf‐MOL) via carboxylate coordination, ALA/Hf‐MOL enhanced ALA delivery and protoporphyrin IX (PpIX) synthesis in mitochondria, and trapped the Hf‐MOL comprising 5,15‐di‐p‐benzoatoporphyrin (DBP) photosensitizers in lysosomes. Light irradiation at 630 nm simultaneously excited PpIX and DBP to generate singlet oxygen and rapidly damage both mitochondria and lysosomes, leading to synergistic enhancement of the PDT efficacy. The dual‐organelle‐targeted ALA/Hf‐MOL outperformed Hf‐MOL in preclinical PDT studies, with a 2.7‐fold lower half maximal inhibitory concentration in cytotoxicity assays in vitro and a 3‐fold higher cure rate in a colon cancer model in vivo. We report a dual‐organelle‐targeted nanoplatform ALA/Hf‐MOL for photodynamic therapy by conjugating 5‐aminolevulinic acid (ALA) to a 2D Hf12‐based metal‐organic nanophotosensitizer (Hf‐MOL). Upon endocytosis, ALA is released from Hf‐MOL and accumulates in mitochondria for porphyrin IX (PpIX) synthesis, while Hf‐MOL is retained in lysosomes. Light irradiation excites both PpIX and Hf‐MOL to elicit potent cytotoxicity and antitumor responses.