Near-infrared target enhanced peripheral clearance of amyloid-β in Alzheimer's disease model

Clearance of peripheral amyloid-β (Aβ) has been demonstrated particularly promising for overcoming the blood-brain barrier (BBB) hurdle to remove brain-derived Aβ associated with Alzheimer's disease (AD). However, currently used therapeutic agents targeting peripheral Aβ cannot simultaneously achieve plasma Aβ enrichment and enhanced clearance, which may result in poor bioavailability and rather low efficacy. Moreover, most of therapeutic agents usually promote the unfavorable aggregation of Aβ. Herein, we construct a near-infrared (NIR) regulated surface-transformable and target peptide-guided upconversion platform (UCNP/ONA-P/K), serving as a safe and effective way for Aβ clearance. Taking advantage of extended blood circulation, high selectivity toward Aβ, and surface-transformable property, such UCNP/ONA-P/K can address the challenges of peripheral Aβ clearance by a combination of enhancing the enrichment of plasma Aβ, preventing the unfavorable aggregation of Aβ and simultaneously facilitating the hepatic clearance of the captured Aβ. After verified by a series of systematic toxicity evaluation, cell uptake, deep tissue penetration, and hemolytic experiments, in vivo studies demonstrate that UCNP/ONA-P/K can efficiently decrease brain Aβ burden and reverse memory deficits in 3xTg-AD mice. Overall, this NIR multi-functional design provides a new biocompatible and efficient way for Aβ removal, which will promote the application of peripheral clearance of Aβ for AD treatment.