Activatable NIR-IIb Nanosensor for Visualizing Brain HClO to Monitor Parkinson’s Disease

Parkinson's disease (PD) is a complex neurodegenerative disorder. Currently, the early diagnosis and treatment of PD are often hindered by significant subjectivity in clinical assessments from both patients and physicians. Hypochlorous acid (HClO), a representative reactive oxygen species, has been widely recognized as closely linked to the pathological mechanisms underlying PD. Thus, we developed a HClO-activated NIR-IIb fluorescent probe, SQ6-RENPs, which is functionalized with the VHP peptide to enable blood-brain barrier (BBB) crossing for monitoring cerebral HClO levels associated with PD progression. The small-molecule SQ6, exhibiting strong absorption at approximately 808 nm, was rationally designed to modulate the NIR-IIb emission of rare-earth nanoparticles (RENPs) via an absorption competition-induced emission (ACIE) mechanism. The probe exhibited excellent sensitivity toward HClO, high selectivity over other analytes, and remarkable stability under physiological conditions. Furthermore, SQ6-RENPs can effectively cross the BBB and accumulate in brain parenchyma through specific binding of the VHP peptide to receptors on brain endothelial cells. These properties render the probe highly suitable for <i>in vivo</i> imaging of cerebral HClO. As expected, SQ6-RENPs successfully revealed the severity of PD and evaluated the therapeutic efficacy of clinically used drugs by real-time monitoring of HClO levels in the brains of PD model mice. This probe offers a promising objective and accurate approach for PD diagnosis and provides a faster strategy for drug evaluation in preclinical research.