MOF-based nanoparticles for tumor-targeted protein degradation and photodynamic therapy induce enhanced anti-tumor immunity

Combining proteolysis targeting chimeras (PROTACs) with photodynamic therapy (PDT) is a promising strategy for cancer treatment. However, the therapeutic efficacy is impaired due to the poor water solubility or the unsatisfactory tumor distribution of drugs. Herein, we developed a Hyaluronan (HA) coating MOF-based nanoplatform (ZMCH) to achieve the combined therapy of PROTACs and PDT with tumor-specific delivery and local drug release. The PROTACs molecules and photosensitizers could be easily wrapped into the nanoparticles via the self-assembly of zinc ions and 2-methylimidazole, which is a universal encapsulation approach for the conventional PROTACs or photosensitizers. As a proof-of-concept, we demonstrated that the designed ZMCH nanoreactor effectively suppresses tumor growth in the 4T1-tumor-bearing mice model, resulting from the synergistic effect of MZ1-mediated protein degradation and the Ce6-mediated reactive oxygen species (ROS) damage. Importantly, the ZMCH-induced therapy exhibited the enhanced antitumor T-cell immunity by regulating immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor metastasis in the lungs. This work thus provides a novel approach and insights for the combination therapy of protein degradation and PDT in clinical cancer treatment.