A Brain-Targeting Nanoprobe for On-Site BACE1 Detection and Reversal of Microglia-Derived Neuroinflammation

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme that when abnormally expressed leads to the overproduction of β-amyloid protein (Aβ). Lead (Pb) exposure exacerbates Aβ accumulation by upregulating BACE1 levels, increasing the risk of cognitive impairments and neurodegenerative diseases. Additionally, Pb-induced elevation of BACE1 is implicated in immune regulation, influencing microglial polarization and neuroinflammation. To address this, we developed a glucosylated enzyme-responsive nanoprobe for BACE1 detection and neuroinflammation alleviation. Utilizing a fluorescence resonance energy transfer (FRET) platform, polydopamine (PDA) nanoparticles were designed to quench the near-infrared emission of donor IR780, conjugated to a BACE1-specific peptide substrate (CK-9). The selective cleavage of CK-9 by BACE1 restored the fluorescence of IR780, exhibiting clear linearity with BACE1 concentrations from 60 to 125 ng/mL and achieving a detection limit of 90.8 pM. The high reductive activity of catechol and quinone groups on PDA, combined with curcumin, provided efficacious ROS scavenging, promoting the polarization of microglia from a pro-inflammatory to an anti-inflammatory state. Moreover, these nanoprobes were specifically designed to cross the blood-brain barrier via GLUT1-mediated targeting, enabling the highly efficient and targeted reaction of Pb-induced BACE1 upregulation in vivo. This multifunctional approach expands the clinical potential of BACE1-targeted diagnostic and therapeutic strategies for neurodegenerative diseases.