光动力疗法（PDT）的功效取决于光敏剂的亚细胞定位。在此，我们报告了一种双细胞器靶向纳米颗粒平台，可增强癌症的PDT。通过将5-氨基戊酸（ALA）通过羧酸酰基配位移植到基于Hf12的纳米金属有机层（Hf-MOL）上，ALA/Hf-MOL增强了ALA的输送和线粒体内原卟啉IX（PpIX）的合成，并将包含5,15-二-p-苯甲酸基卟啉（DBP）光敏剂的Hf-MOL陷入溶酶体。630 nm的光照射同时激发PpIX和DBP，产生单一氧并快速损伤线粒体和溶酶体，从而协同增强PDT的功效。双细胞器靶向ALA/Hf-MOL在临床前PDT研究中表现优异，在体外细胞毒性实验中具有2.7倍更低的半数抑制浓度，而在体内结肠癌模型中具有3倍的治愈率。©2023 Wiley-VCH GmbH。

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 single 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.© 2023 Wiley-VCH GmbH.