Herein we report the design of a bacteriochlorin-based nanoscale metal–organic framework, Zr-TBB, for highly effective photodynamic therapy via both type I and type II mechanisms. The framework of Zr-TBB stabilizes 5,10,15,20-tetra­(p-benzoato)­bacteriochlorin (TBB) ligands toward oxygen and light via geometrical constraint. Upon 740 nm light irradiation, Zr-TBB efficiently generates various reactive oxygen species, including singlet oxygen, superoxide anion, hydrogen peroxide, and hydroxyl radicals, to afford superb antitumor efficacy on mouse models of breast and colon cancers, with cure rates of 40% and 60%, respectively.

Nanoscale metal–organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy–radiodynamic therapy (RT-RDT). Herein, we report surface modification of a Hf-DBP nMOF for the co-delivery of a hydrophobic small-molecule toll-like receptor 7 agonist, imiquimod (IMD), and a hydrophilic macromolecule, anti-CD47 antibody (αCD47), for macrophage modulation and reversal of immunosuppression in tumors. IMD repolarizes immunosuppressive M2 macrophages to immunostimulatory M1 macrophages, while αCD47 blocks CD47 tumor cell surface marker to promote phagocytosis. Upon X-ray irradiation, IMD@Hf-DBP/αCD47 effectively modulates the immunosuppressive tumor microenvironment and activates innate immunity to orchestrate adaptive immunity when synergized with an anti-PD-L1 immune checkpoint inhibitor, leading to complete eradication of both primary and distant tumors on a bilateral colorectal tumor model. nMOFs thus provide a unique platform to co-deliver multiple immunoadjuvants for macrophage therapy to induce systematic immune responses and superb antitumor efficacy.

Checkpoint blockade immunotherapy (CBI) awakes a host innate immune system and reactivates cytotoxic T cells to elicit durable response in some cancer patients. Now, a cationic nanoscale metal–organic framework, W‐TBP, is used to facilitate tumor antigen presentation by enabling immunogenic photodynamic therapy (PDT) and promoting the maturation of dendritic cells (DCs). Comprised of dinuclear WVI secondary building units and photosensitizing 5,10,15,20‐tetra(p‐benzoato)porphyrin (TBP) ligands, cationic W‐TBP mediates PDT to release tumor associated antigens and delivers immunostimulatory CpG oligodeoxynucleotides to DCs. The enhanced antigen presentation synergizes with CBI to expand and reinvigorate cytotoxic T cells, leading to superb anticancer efficacy and robust abscopal effects with >97 % tumor regression in a bilateral breast cancer model.

As a monolayered version of nanoscale metal−organic frameworks (nMOFs), nanoscale metal− organic layers (nMOLs) represent an emerging class of highly tunable two-dimensional materials for hierarchical functionalization and with facile access to analytes. Here we report the design of the first nMOL-based biosensor for ratiometric pH and oxygen sensing in mitochondria. Cationic Hf 12 -Ru nMOL was solvothermally synthesized by laterally connecting Hf 12 secondary building units (SBUs) with oxygen-sensitive Ru(bpy) 3 2+ -derived DBB-Ru ligands (bpy = 2,2′-bipyridine). The Hf 12 -Ru nMOL was then covalently functionalized with pH-sensitive fluorescein isothiocyanate and pH/oxygen-independent Rhodamine-B isothiocyanate through thiourea linkages to afford Hf 12 -Ru-F/R as a mitochondria-targeted ratiometric sensor for pH and O 2 in live cells. High-resolution confocal microscope imaging with Hf 12 -Ru-F/R revealed a positive correlation between pH and local O 2 concentration in mitochondria. Our work shows the potential of nMOL-based ratiometric biosensors in sensing and imaging of biologically important analytes in live cells.

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