...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.