Abstract
Most photosensitizers (PSs) mediate type II photodynamic therapy (PDT) via energy transfer to produce singlet oxygen. However, this mechanism is oxygen-dependent and less effective in hypoxic tumors. Type I PDT, which generates radical reactive oxygen species such as superoxide through electron transfer, is more hypoxia-tolerant, yet molecular design strategies remain limited. Herein, we report an iminium-linked hyperporphyrin covalent organic framework (IH-COF) that facilitates efficient type I PDT via a photoredox process. In a one-pot synthesis, trimethyloxonium tetrafluoroborate simultaneously quaternizes imine bonds to introduce electron acceptors and protonates porphyrins, red-shifting the Q-band to 725 nm via the hyperporphyrin effect. Mechanistic studies reveal that photoinduced electron transfer from hyperporphyrin units to iminium ions generates α-amino radicals, which reduce oxygen to superoxide while regenerating iminium ions. The oxidized hyperporphyrins are then reduced by biomolecules such as 1,4-dihydronicotinamide adenine dinucleotide, sustaining the photocatalytic cycle. Consequently, IH-COF exhibits excellent PDT performance under both normoxic and hypoxic conditions and elicits potent antitumor efficacy in colorectal and triple-negative breast cancer models in female mice. This study highlights the potential of COFs as versatile and biocompatible platforms for synergistic photomedicine applications.
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All data supporting the findings of this study are available from the corresponding author.
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Acknowledgements
We acknowledge the National Cancer Institute (1R01CA253655) for funding support. Dr Yubin Fu gratefully acknowledges the GWK support for funding this project by providing computing time through the Center for Information Services and HPC (ZIH) at TU Dresden.
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Z.Z., Y.X. and W.L. conceived the idea and designed the project. W.L. supervised the project. Z.Z. and Y.X. performed the experimental works. Yingjie and Z.W. assisted in mechanistic analysis experiments. C.D. assisted in the simulations. J.L. performed morphological analysis. Yubin performed high-level theoretical calculations. Q.S., C.H., and G.E. performed transient absorption spectroscopy measurements. Z.Z., Y.X. and W.L. wrote the paper. All authors discussed the results.
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Zhou, Z., Xiong, Y., Wang, Z. et al. Iminium-linked hyperporphyrin covalent organic framework mediates type I photodynamic therapy via a photoredox process. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71240-2
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DOI: https://doi.org/10.1038/s41467-026-71240-2
