Abstract
Incorporating sulfur atoms into photosensitizers (PSs) has been well-established to populate triplet states and increase singlet oxygen ((1)O(2)) production when exposed to light. In this work, we found that progressive thiolation of porphyrin β-periphery does promote intersystem crossing (ISC) between triplets and singlets, as seen in the excited state dynamics in dichloromethane or PS nanoparticles in water. However, in the latter case, more sulfur substitution deactivates (1)O(2) photosensitization, in contrast to the expected trend observed in dichloromethane. This observation was further supported by photocytotoxicity studies, where (1)O(2) photosensitization was switched off in living cells and multicellular spheroids despite being switched on in in vivo mice models. To understand the inconsistency, we performed molecular dynamics simulation and time-dependent density functional theory calculations to investigate possible aggregation and related excited states. We found that the extent of thiolation could regulate molecular packing inside nanoparticles, which gradually lowers the energy levels of triplet states even lower than that of (1)O(2) and, in turn, alters their energy dissipation pathways. Therefore, this study provides new insights into the design of metal-free PSs and sheds light on the excited state dynamics in aqueous media beyond the molecular level.