Fluorination‐Induced Multi‐Enhancement of a Nano‐Photosensitizer for Deep Photodynamic Therapy against Hypoxia Tumor

Abstract Organic dyes hold great promise for application in photodynamic therapy (PDT). However, they currently face challenges such as inadequate photodynamic activity, limited tumor penetration, and constraints imposed by tumor hypoxia. Here, a facile and efficient strategy is presented for multi‐enhanced PDT through the fluorination of a squarylium indocyanine dye‐based photosensitizer (FCy). The amphiphilic FCy features perfluorooctane and PEG‐biotin moieties conjugated to a squarylium indocyanine core. In aqueous environments, FCy spontaneously self‐assembles into stable nano‐sized photosensitizers (FCy NPs), demonstrating a high oxygen loading ability attributable to the presence of perfluoroalkyl groups. Consequently, the aggregation of squarylium indocyanine dyes remarkably boosts the photodynamic effect, yielding a 15‐fold improvement in singlet oxygen quantum yield. Owing to the perfluoroalkyl group, FCy NPs exhibit increased endoplasmic reticulum (ER)‐ accumulating abilities, which further induce ER stress upon laser irradiation and enhance the PDT effect. Furthermore, the superior deep tumor penetration ability of FCy NPs is confirmed through both in vitro and in vivo studies. With efficient oxygen supply to the deep tumor regions, FCy NPs demonstrate potent imaging‐guided PDT against hypoxia tumors. The study substantiates the enhanced ER‐accumulating ability of the perfluoroalkyl group and presents a facile fluorination strategy for the multi‐enhancement of photosensitizers.