Supramolecular Reactivation of Quenched Silicon Naphthalocyanine for NIR-II Fluorescence-Guided Type I/II Photodynamic Monotherapy

Silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) (SiNc) possesses intense near-infrared absorption, promising NIR-II emission, and a high reactive oxygen species quantum yield in its monomeric state. However, its potential as a NIR-II fluorescent photosensitizer has been long hindered by aggregation-caused quenching in aqueous environments. Herein, we report a supramolecular engineering strategy to overcome this limitation by precisely tuning the molecular packing of SiNc within a biocompatible DSPE-PEG 2000 matrix. Through systematic optimization of the dye-to-matrix ratio, initial dye concentration, and solvent composition, we obtain optimized nanoparticles (SiNc NPs) that effectively disrupt tight π–π stacking. Compared to severely quenched control nanoparticles (Ctrl-NPs), SiNc NPs exhibit a 3-fold enhancement in fluorescence quantum yield (4.2% vs 1.4%), alongside 17.7-fold and 8.7-fold increases in 1 O 2 (Φ Δ = 10.6% vs 0.6%) and O 2 •– generation, respectively. Consequently, SiNc NPs deliver potent NIR-II fluorescence-guided photodynamic efficacy in vivo. Following a single low-dose intravenous injection and one session of 781 nm laser irradiation, SiNc NPs achieve near-complete 4T1 tumor eradication, showing improved efficacy compared to both a clinical photosensitizer (Ce6) and Ctrl-NPs under the tested conditions. This work establishes a programmable supramolecular paradigm for reactivating highly quenched, aggregation-prone chromophores, offering a practical alternative to complex de novo synthesis in the pursuit of high-performance NIR-II fluorescent photosensitizers capable of effective photodynamic monotherapy.