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 dysfu...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 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβremoval.In AD model mice,this intervention significantly reduced brain Aβlevels by nearly 45%and increased plasma Aβlevels by 8-fold within 2 h,as measured by ELISA.Multiple imaging techniques confirmed the reduction in brain Aβsignals after treatment.Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory,with performance levels comparable to those of wild-type mice.These cognitive benefits 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 trafficking level.Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective.We establish a compelling case for BBB modulation and LRP1-mediated Aβclearance as a transformative foundation for future AD therapies.展开更多
基金supported by the National Key R&D Program of China(2022YFC2009900)the Alzheimer’s Association New to the Field award,ERC Consolidator grant H2020-ERC-2018-CoG(769798 CheSSTag)+1 种基金the Plan de Recuperacion Nacional Biotech for Health Project(ADNano),Activitat científica dels grups de recerca de Catalunya(SGR-Cat 2021)the Spanish Research Agency Proyectos I+D+I PID2020-119914RB-I00。
文摘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 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβremoval.In AD model mice,this intervention significantly reduced brain Aβlevels by nearly 45%and increased plasma Aβlevels by 8-fold within 2 h,as measured by ELISA.Multiple imaging techniques confirmed the reduction in brain Aβsignals after treatment.Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory,with performance levels comparable to those of wild-type mice.These cognitive benefits 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 trafficking level.Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective.We establish a compelling case for BBB modulation and LRP1-mediated Aβclearance as a transformative foundation for future AD therapies.
