MOFs‐Based Nanoagents Enable Sequential Damage to Cancer‐Associated Fibroblast and Tumor Cells for Phototriggered Tumor Microenvironment Regulation

Abstract A composite nanoagent capable of phototriggered tumor microenvironment (TME) regulation is developed based on copper (II) metal‐organic frameworks (MOFs) with encapsulation of blebbistatin (Bb) and surface modification of fibroblast activation protein‐αtargeted peptide (Tp). Tp enables active targeting of the nanoagents to cancer‐associated fibroblast (CAF) while near‐infrared light triggers Cu²⁺‐to‐Cu⁺ photoreduction in MOFs, which brings about the collapse of MOFs and the release of Bb and Cu⁺. Bb mediates photogeneration of hydroxyl radicals (•OH) and therefore inhibits extracellular matrix production by inducing CAF apoptosis, which facilitates the penetration of nanoagent to deep tumor tissue. The dual‐channel generation of •OH based on Bb and the Cu⁺ species, via distinct mechanisms, synergistically reinforces oxidative stress in TME capable of inducing immunogenic cell death, which activates the antitumor immune response and therefore reverses the immunosuppressive TME. The synergistic antitumor phototherapy efficacy of such a type of nanoagent based on the abovementioned TME remodeling is unequivocally verified in a cell‐derived tumor xenograft model.