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.
Xu et al. (2025) studied this question.