Bioactive Metal–Organic Frameworks with Specific Metal–Nitrogen (M–N) Active Sites for Efficient Sonodynamic Tumor Therapy

Sonodynamic therapy (SDT) offers an efficient noninvasive strategy for cancer treatment. However, the efficiency of SDT is limited by the structural and physicochemical properties of ultrasound (US)-sensitive agents. Here, we discover the combination of bioactivity and sonodynamic properties of zeolite imidazolium framework-8 nanocrystals (ZIF-8 NCs) for efficient tumor therapy. ZIF-8 NCs are susceptible to biodegradation to release zinc ions (Zn2+) triggered by the weakly acidic tumor microenvironment, demonstrating the bioactivity to induce apoptosis in cancer cells. Density functional theory calculations combined with experiments revealed that the unsaturated zinc–nitrogen (Zn–N) active sites on the surface of ZIF-8 NCs allow an enhanced electron transfer via ligand to metal charge transfer bands from the highest occupied molecular orbitals to the lowest unoccupied molecular orbitals. This process is critical for the generation of reactive oxygen species by metal–organic frameworks (MOFs) under US irradiation. In vivo experiments show that ZIF-8 NCs exhibit high tumor inhibition efficiency (84.6%) as both a bioactive anticancer agent and a sonosensitizer. We believe that this study can expand the application of MOFs and contribute to a better understanding of the mechanism of action of sonosensitizers.