Controlled Electron Transfer: Implementing a Reservoir-Pump-Integrated Strategy to Develop a Type I Photosensitizer for Evoking Long-Term Tumor Immunological Memory

Type I photosensitizers (PSs), due to reduced dependence on O2, have outstanding prospects for cancer treatment. However, it is difficult to manipulate electron transfer of molecules during excited state transitions (T1–S0), which makes it a challenging task to systematically create type I PSs, especially with a deficiency of an instructive molecular construction strategy. Herein, for the first time, we proposed the “electron reservoir-pump-integrated” molecular design strategy, that is, “electron reservoir” and “electron pump” were dexterously fused in one appropriate dye, which greatly facilitated the creation of type I PS molecules through the manipulation of spatial electron flow (verified by the density functional theory and spectral experiments). On this basis, we constructed a series of organic small-molecule type I PSs; especially, the prominent type I PS Cy5-NF could specifically produce a large amount of O2•– under 660 nm laser irradiation. Notably, without the sulfonic acid groups (electron reservoir) or the electron-withdrawing group (electron pump), both derivatives of Cy5-NF are unable to generate O2•–, which fully validated the above strategy. More encouragingly, Cy5-NF could effectively destroy cytomembranes under irradiation and further lead to pyroptosis of tumor cells, which not only ablated the primary/distant tumors but also halted tumor metastasis to the different organs via enhancing CD4+ and CD8+ T cell infiltration-mediated long-term immunological memory. Notably, the “electron reservoir-pump-integrated” strategy represents a kind of modular approach for constructing organic small-molecule type I PSs, potentially offering valuable guidance for future type I PS development.