Authors: Guangxiao Yao, Junfeng Miao, Yingying Huo, Wei Guo
Published: 2025-03-11
Source: Full article
AbstractIt is highly desired to achieve Type‐I photosensitizer (PS) to overcome the hypoxic limitation found in most clinically used PSs. Herein, a new heavy‐atom‐free Type‐I PS T‐BNCy5 is presented by incorporating a biotin‐modified naphthalimide (NI) unit into the meso‐position of a N‐benzyl‐functionalized, strongly photon‐capturing pentamethine cyanine (Cy5) dye. Such molecular engineering induces a rigid orthogonal geometry between NI and Cy5 units by introducing an intramolecular sandwich‐like π–π stacking assembly, which effectively promotes intersystem crossing (ISC) and greatly extends the triplet‐state lifetime (τ = 389 µs), thereby markedly improving the superoxide (O2•−)‐generating ability. In vitro assays reveal that T‐BNCy5 specifically accumulates in mitochondria, where it not only generates O2•− under photoirradiation but also induces the burst of the most cytotoxic hydroxy radical (HO•) by a cascade of biochemical reactions, ultimately triggering cell ferroptosis with the IC50 value up to ≈0.45 µm whether under normoxia or hypoxia. In vivo assays manifest that, benefiting from its biotin unit, T‐BNCy5 displays a strong tumor‐targeting ability, and after a single PDT treatment, it can not only ablate the tumor almost completely but also be cleared from the body through biosafe urinary excretion, indicating its potential for future clinical translation.