Rabies is a viral disease with an almost 100% fatality rate, primarily transmitted through bites from infected animals, with a long incubation period and no effective clinical treatments to date. Herein, we developed the first fluorescent nanotheranostic probe in the second near-infrared (NIR-II) window capable of efficiently crossing the blood–brain barrier (BBB), precisely targeting rabies virus (RABV), and enabling safe photodynamic therapy (PDT). This probe is based on a novel NIR-II organic polyacetylene fluorophore, DK, which self-assembles via a click reaction with a nanoparticle carrier, N3-PEG2000-R, that we synthesized with a high biocompatibility and BBB permeability. The probe surface is further modified with an aptamer that specifically binds to RABV glycoprotein (RVG), resulting in our final nanotheranostic probe, DK@RA-PEG. Upon intravenous injection into mice, it effectively crosses the BBB, localizes to the infection site, and binds to the RVG, allowing for real-time NIR-II fluorescence imaging. Additionally, it efficiently converts light energy into chemical energy without generating thermal effects, ensuring safe and effective PDT. This advanced nanotheranostic probe integrates precise targeting, deep-tissue imaging, and safe therapy, making it a promising candidate for future clinical applications in rabies treatment.

https://doi.org/10.1021/jacs.5c04975