Type I BODITh Photosensitizers with Twisted Conformation for Augmented Photodynamic Therapy and FOXO1-Involved Apoptosis

Developing targeted type I photosensitizers with low oxygen-dependence is essential to overcome tumor hypoxia and address the short diffusion radius of free radicals in photodynamic therapy (PDT). Herein, two Boron dithiazolemethene (BODITh)-derivatives, SBDP-1 and SBDP-2 with different numbers of thiophene units, were designed as mitochondria-targeted type I photosensitizers with significant ·OH generation. Through theoretical calculations, the additional thiophene unit in SBDP-2 induced a torsional conformation with a smaller overlap integral of holes and electrons than SBDP-1, resulting in an increased spin–orbit coupling (SOC) constant with a decreased singlet–triplet energy gap (Δ E ST ), thereby promoting the intersystem crossing (ISC) process. Moreover, through a molecular docking study, SBDP-2 NPs could bind to miR-96 via hydrophobic interaction and trigger the forkhead box protein O1 (FOXO1) involved pathway to accelerate cell apoptosis. This work presented innovative type I photosensitizers with twisted conformation for efficient cancer PDT to conquer tumor hypoxia.