"Dual-Boosting" Strategy to Enhance Radical Generation of Photosensitizer for Mitochondria-Targeted Phototherapy

Organelle-targeted photodynamic therapy (PDT) shows substantial promise for precision tumor treatment. However, the clinical translation of oxygen-independent photosensitizers (PSs) designed for mitochondrial localization remains challenging. Herein, we propose a "dual-boosting" strategy to enhance the type-I PDT efficacy of mitochondria-targeted PSs. The first boost leverages multi-branched donor/π-bridge engineering to develop a series of mitochondria-targeted pyrido cyanines. Among them, McL3 displays broad visible-light absorption and a reduced singlet-triplet energy gap (ΔE _S1-T3 = 0.24 eV), which collectively lead to a 4.2-fold increase in superoxide anion radical (•O₂ ^-) generation compared to McL1. The second boost is achieved through the self-assembly of McL3 with human serum albumin (HSA) into McL3@HSA nanoparticles (~40 nm). This confinement further narrows ΔE _S1-T2 to 0.08 eV, amplifying •O₂ ^- production by 20.3-fold. Mechanistic studies indicate that HSA confinement modulates molecular conformation and promotes ISC efficiency from 33% to 52%, enabling efficient •O₂ ^- generation. Upon white-light irradiation, McL3@HSA selectively accumulates in mitochondria, inducing apoptosis and effectively inhibiting tumor growth even under hypoxic conditions. This work establishes a "dual-boosting" paradigm for the rational design of mitochondria-targeted, hypoxia-tolerant PSs, offering a promising avenue for clinical phototheranostics.