Immunotherapy has become a promising cancer therapy, but only works for a subset of cancer patients. Immunogenic photodynamic therapy (PDT) can prime cancer immunotherapy to increase the response rates, but its efficacy is severely limited by tumor hypoxia. Here we report a nanoscale metal-organic framework, Fe-TBP, as a novel nanophotosensitizer to overcome tumor hypoxia and sensitize effective PDT, priming non-inflamed tumors for cancer immunotherapy. Fe-TBP was built from iron-oxo clusters and porphyrin ligands and sensitized PDT under both normoxic and hypoxic conditions. Fe-TBP mediated PDT significantly improved the efficacy of anti-programmed death-ligand 1 (α-PD-L1) treatment and elicited abscopal effects in a mouse model of colorectal cancer, resulting in >90% regression of tumors. Mechanistic studies revealed that Fe-TBP mediated PDT induced significant tumor infiltration of cytotoxic T cells.

Selective delivery of photosensitizers to mitochondria of cancer cells can enhance the efficacy of photodynamic therapy (PDT). Though cationic Ru-based photosensitizers accumulate in mitochondria, they require excitation with less penetrating short-wavelength photons, limiting their application in PDT. We recently discovered X-ray based cancer therapy by nanoscale metal–organic frameworks (nMOFs) via enhancing radiotherapy (RT) and enabling radiodynamic therapy (RDT). Herein we report Hf-DBB-Ru as a mitochondria-targeted nMOF for RT-RDT. Constructed from Ru-based photosensitizers, the cationic framework exhibits strong mitochondria-targeting property. Upon X-ray irradiation, Hf-DBB-Ru efficiently generates hydroxyl radicals from the Hf6 SBUs and singlet oxygen from the DBB-Ru photosensitizers to lead to RT-RDT effects. Mitochondria-targeted RT-RDT depolarizes the mitochondrial membrane to initiate apoptosis of cancer cells, leading to significant regression of colorectal tumors in mouse models. Our work establishes an effective strategy to selectively target mitochondria with cationic nMOFs for enhanced cancer therapy via RT-RDT with low doses of deeply penetrating X-rays.

Nanoscale metal−organic frameworks (nMOFs) have shown great potential as nanophotosensitizers for photodynamic therapy (PDT) owing to their high photosensitizer loadings, facile diffusion of reactive oxygen species (ROSs) through their porous structures, and intrinsic biodegradability. The exploration of nMOFs in PDT, however, remains limited to an oxygen-dependent type II mechanism. Here we report the design of a new nMOF, Ti-TBP, composed of Ti-oxo chain secondary building units (SBUs) and photosensitizing 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) ligands, for hypoxia-tolerant type I PDT. Upon light irradiation, Ti-TBP not only sensitizes singlet oxygen production, but also transfers electrons from excited TBP* species to Ti 4+based SBUs to afford TBP •+ ligands and Ti 3+ centers, thus propagating the generation of superoxide, hydrogen peroxide, and hydroxyl radicals. By generating four distinct ROSs, Ti-TBP-mediated PDT elicits superb anticancer efficacy with >98% tumor regression and 60% cure rate. Communication pubs.acs.org/JACS

Metal-organic layers (MOLs), a free-standing monolayer version of two-dimensional metal-organic frameworks (MOFs), have emerged as a new class of 2D materials for many potential applications. Here we report the design of a new photosensitizing MOL, Hf-Ru, based on Hf secondary building units (SBUs) and [Ru(bpy)] (bpy = 2,2'-bipyridine) derived dicarboxylate ligands. After modifying the SBU surface of Hf-Ru with M(bpy)(CO)X (M = Re and X = Cl or M = Mn and X = Br) derived capping molecules through carboxylate exchange reactions, the resultant Hf-Ru-Re and Hf-Ru-Mn MOLs possess both [Ru(bpy)] photosensitizers and M(bpy)(CO)X catalysts for efficient photocatalytic CO reduction. The proximity of the MOL skeleton to the capping ligands (1-2 nm) facilitates electron transfer from the reduced photosensitizer [Ru(bpy)] to M(bpy)(CO)X (M = Re, Mn) catalytic centers, resulting in CO reduction turnover numbers of 8613 under artificial visible light and of 670 under sunlight. MOLs thus represent a novel platform to assemble multifunctional materials for studying artificial photosynthesis.

Metal-organic frameworks (MOFs) have been extensively used for single-site catalysis and light harvesting, but their application in multicomponent photocatalysis is unexplored. We report here the successful incorporation of an Ir photoredox catalyst and a Ni cross-coupling catalyst into a stable Zr MOF, Zr -Ir-Ni, to efficiently catalyze C-S bond formation between various aryl iodides and thiols. The proximity of the Ir and Ni catalytic components to each other (ca. 0.6 nm) in Zr -Ir-Ni greatly facilitates electron and thiol radical transfers from Ir to Ni centers to reach a turnover number of 38 500, an order of magnitude higher than that of its homogeneous counterpart. This work highlights the opportunity in merging photoredox and organometallic catalysts in MOFs to effect challenging organic transformations.