Cytotoxic crosslinker-loaded indocyanine green nanoparticle for near-infrared fluorescence imaging-guided chemo-photothermal eradication of triple-negative breast cancer

Crosslinkers are conventionally used for cell fixation due to their crosslinking ability, although they are cytotoxic. Given this cytotoxicity, their therapeutic potential as anticancer agents remains largely unexplored. Herein, we repurpose a bifunctional crosslinker, 1,4-phenylene diisothiocyanate (PDITC), which self-assembles with indocyanine green (ICG) into a biocompatible nanoplatform (PDITC@ICG) for treating triple-negative breast cancer. In vitro, PDITC@ICG with laser irradiation achieves a 3.5-fold potency improvement over free PDITC. In vivo in a 4T1 tumor model, PDITC@ICG with laser reduces tumor volume by 82.1% and achieves complete regression in 60% of mice, significantly outperforming ICG with laser and PDITC alone. Mechanistically, the synergy may arise from photothermal-augmented cytotoxicity of the crosslinker and nanocarrier-facilitated cellular uptake. Notably, comprehensive hematological, hepatorenal, and histopathological analyses reveal no systemic toxicity or organ damage. This work establishes a paradigm for repurposing a conventional crosslinker as an effective anticancer agent within an imaging-guided photothermal nanoplatform, offering a promising and synergistic strategy for precision oncology.