Naphthalimide-Based Type-I Nano-Photosensitizers for Enhanced Antitumor Photodynamic Therapy: H₂S Synergistically Regulates PeT and Self-Assembly

Photodynamic therapy (PDT) relies on a combination of light and photosensitizers (PSs) to achieve local control over cancerous lesions. However, it is subject to limitations, including tumor hypoxia, low tumor targeting, off-target phototoxicity, and always-on fluorescence. Here, we propose a design strategy for activated nano-PSs (N-PSs) to simultaneously overcome the limitations of PDT, wherein photoinduced electron transfer (PeT) is coupled with an endogenous H₂S-regulated self-association process to promote Type-I photochemical reactions. Using theoretical calculations, spectral analysis, and microscopic imaging, we verified the generation of self-assembly and occurrence of PeT. And it was also shown that H₂S could synergistically inhibit the PeT and self-assembly, reflecting by a 21-fold increase in fluorescence intensity at 635 nm and 35-fold enhancement of the Type-I photochemical reaction as inferred from O₂⁻ generation. Moreover, the most promising self-assembled N-PS, Ts3-ONB, was found to almost completely inhibit tumor growth in mice under two-photon excitation through the synergistic regulation of PeT and self-assembly by endogenous H₂S (V_{14 days}^{Ts3-ONB+ Light group}/V_{14 days}^{Control group} ≈ 0.02). As such, the synergistic combination of PeT and self-assembly is an effective design strategy for developing advanced N-PSs that can address some current PDT limitations.