Mitochondria‐Targeted Nanoscale MOFs for Improved Photodynamic Therapy

Abstract Due to the existence of hypoxic microenvironment, the efficacy of photodynamic therapy (PDT) is frequently weakened. As a result, targeted treatment toward oxygen‐rich mitochondria is considered as a promising cancer therapy. Herein, both triphenylphosphine (TPP) and folic acid (FA) are simultaneously grafted onto nanoscale metal‐organic frameworks (NMOFs) to realize dual‐targeting delivery of the nanoplatforms into cancer cells and their mitochondria via the proposed phosphorylation modification strategy. A large amount of highly efficient photosensitizer of porphyrinic molecules is integrated into the NMOFs with a uniform particle size of about 65 nm. Thanks to the strong Zr−O−P bonding, a dense coverage of phosphonate‐conjugating targeting molecules on NMOFs is obtained and each surficial unsaturated Zr−O cluster is adequately occupied. The resultant dual‐targeting NMOFs feature high biostability and biocompatibility, as well as improved cellular uptake and mitochondrial accumulation. The PDT efficacy of these dual‐targeting NMOFs is significantly improved with a low IC₅₀ of 0.74 μM upon 10 min light radiation, which is at least four times higher than that of non‐targeting counterparts. This phosphorylation strategy would be hopeful for immobilizing a variety of biogenic groups on NMOFs to make them targetable to various specific organelles and to improve the therapy efficacy on related diseases.