Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood–brain barrier transport

Abstract

The blood‒brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer’s disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 traf cking toward transcytosis and thereby upregulating its expression to promote ef cient Aβ removal. In AD model mice, this intervention signi cantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 h, as measured by ELISA. Multiple imaging techniques con rmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited signi cant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive bene ts persisted for up to 6 months post-treatment. This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane traf cking level. Our ndings also reaf rm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions signi cantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.