Trimerization-Enhanced NIR-II/Photoacoustic Nanoprobes for Precision Osteosarcoma Imaging

The integration of photoacoustic imaging (PAI) and near-infrared II (NIR-II) fluorescence imaging holds transformative potential for cancer diagnostics but faces challenges in developing high-performance dual-modal contrast agents. We report tH7@CT8, an organic nanoprobe engineered through fluorophore trimerization to address the photothermal conversion efficiency limitations of small-molecule agents. Trimerization of the [1,2,5]thiadiazolo[3,4-g]quinoxaline fluorophore derivative H7 induced aggregation, suppressing fluorescence quantum yield (0.11% vs 0.42% monomer) while amplifying PTCE to 43.1%. Encapsulation within an osteosarcoma-targeting amphiphilic matrix yielded nanoparticles (72 ± 19 nm) with 4-fold enhanced tumor uptake versus nontargeted controls. In orthotopic osteosarcoma models, tH7@CT8 enabled PAI detection and real-time NIR-II guidance with signal (tumor)-to-background ratios >12:1. This work establishes a molecular design strategy to reconcile depth-resolution trade-offs in oncology while advancing organic contrast agents toward clinical translation.