Diradicaloid-Loaded Polypeptide Nanoparticles for Two-Photon NIR Phototheranostics

Stable organic radicals, with unique electronic transitions from the ground state (D₀) to the doublet excited state (D₁), show promise as high-fluorescence quantum yield dyes. While organic small-molecule photosensitizers (PSs) have advanced for tumor photodynamic therapy (PDT), opportunities exist to enhance their performance and functionality. Herein, we synthesized Thiele's fluorocarbon derivative diradicaloid TFC-I with nearly 100% PLQY and integrated it into amphiphilic polypeptide nanoparticles, P-TI, using a precursor-doping approach. P-TI demonstrated notable features including high photostability, aggregation-induced emission, bright near-infrared fluorescence, substantial quantum yield (37% PLQY), robust near-infrared two-photon absorption (∼400 GM cross section), and superior ROS generation compared to commercial PSs. <i>In vitro</i> and <i>in vivo</i> experiments confirmed that P-TI performed well in mitochondria-targeted PDT, two-photon fluorescence imaging, and biosafety. This work highlights the use of organic stable radicals with precursor-doping for efficient PDT and deep tumor tissue imaging.