pH-Activatable NIR Hemicyaninefor Mitochondria-TargetedCancer Phototheranostics

Photodynamic therapy (PDT) has garnered significant attention for cancer treatment due to its noninvasive nature, reduced drug resistance, and spatiotemporal controllability. However, traditional photosensitizers (PSs) face limitations such as severe systemic phototoxicity and shallow tissue penetration, which hinder the widespread clinical application of PDT. Capitalizing on the strong near-infrared (NIR) absorption and ease of structural modification of hemicyanine, we have designed a pH-activatable NIR hemicyanine PS (LET-15). It is specifically activated in the acid tumor microenvironment, subsequently targeting mitochondria and generating cytotoxic singlet oxygen under 660 nm laser irradiation, which selectively destroys tumor tissues while minimizing damage to healthy tissues. Additionally, it offers activatable fluorescence (FL) imaging with a high signal-to-noise ratio, enabling FL imaging-assisted tumor photoeradication. This study provides valuable guidance for designing tumor-specifically activated NIR PSs for precision PDT.