Rational Design of Near-Infrared Difluoroboron Cyanine Photosensitizers for Lipid Droplet-Targeting Imaging and Tumor Therapy.

Specifically disrupting lipid droplets (LDs) is an effective strategy for ablating tumor cells through photodynamic therapy (PDT). However, most reported LD probes possess short excitation/emission wavelengths, limiting tissue penetration, and LD-targeted theranostic probes remain underdeveloped. In this work, we first developed a family of near-infrared (NIR) charge-neutral and lipid droplet-targeting cyanine photosensitizers by systematically introducing heavy atoms (Br/I) at different sites of electrically neutral BF2-bridged cyanine (BCy5). These BCy photosensitizers retain the characteristic near-infrared absorption (>650 nm) and high molar extinction coefficients of classical cyanine dyes while exhibiting good singlet oxygen quantum yields. Notably, BCy5-Br1-BCy5-Br3 nanoparticles with high LD specificity exhibit significant PDT efficacy at submicromolar concentrations and, by inducing oxidative stress and lipid peroxidation (LPO) accumulation, concurrently trigger apoptosis and ferroptosis, effectively suppressing melanoma growth in vivo. This work provides vital insights into design principles and transformation of LD-targeting NIR cyanine photosensitizers for cancer PDT.