The BSA mediating the proton coupled electron transfer to unlock the photo-generation of hydroxyl in cancer cells

Abstract

The unique attributes of proteins-including their confined nanoscale cavities, abundant redox-active amino acid residues, and excellent biocompatibility-offer significant advantages for constructing protein-based enzymatic systems. However, their potential remains underexplored in photosensitization systems for shifting photosensitization pathways. Here, we report a bovine serum albumin (BSA)-based photosensitizing system, termed TC2@BSA, in which the BSA nanoreactor mediated proton-coupled electron transfer (PCET) to unlock the photogeneration of hydroxyl radicals (•OH) in cancer cells.The photosensitizer TC2, which was inherently incapable of generating •OH, was encapsulated within the subdomain IIA of BSA in a more planar and compact configuration and stabilized by hydrophobic interactions, π-π stacking, and hydrogen bonding. Isotope labeling, electron paramagnetic resonance (EPR), and electrochemical experiments confirmed that the photo-disproportionation of the encapsulated TC2 coupled with the PCET process of the BSA nanoreactor led to the yield of •OH and enhanced the photostability. TC2@BSA generated abundant •OH and demonstrated remarkable photocytotoxicity against cancer cells. This study opens a new avenue for the design of biocompatible protein-based photosensitizers.