Glycoengineered Host-Guest Nanoparticles Potentiate Alzheimer's Disease Therapy via Lesion-Specific Modulation of Tau Pathology.

Tau pathology is a principal driver of cognitive impairment in Alzheimer's disease (AD), but the therapeutic targeting of tau has been hindered by poor brain delivery and a lack of lesion-confined activity. Here, we delineate a pathogenic cascade wherein the impaired dephosphorylation of hyperphosphorylated tau (p-tau) leads to its aggregation, which is amplified by microglia-mediated propagation. To combat this p-tau cascade, we developed a glycoengineered proteolysis targeting chimera (PROTAC) nanoparticle for lesion-specific p-tau modulation therapy. We first synthesized a library of p-tau PROTACs and identified a lead compound (namely, PROTAC-7) that effectively degraded diverse p-tau species across multiple cellular and animal models of tauopathy. The glycoengineered nanoparticles were then prepared by coassembly of galactose/cyclodextrin-grafted polysialic acid with a microglial scavenger PLX and a reactive oxygen species (ROS)-sensitive heterodimer of PROTAC-7 and memantine (an activator of protein phosphatase 2A). Upon systemic administration, the glycoengineered PROTAC nanoparticles achieved brain-targeted delivery of the therapeutics via glycemic-gradient-mediated transport across the blood-brain barrier. Upon activation in ROS-rich AD lesions, the nanoparticles released their payload for spatially confined p-tau degradation and suppression of tau phosphorylation and spread. This coordinated modulation strategy markedly reversed tau pathology, restored synaptic plasticity, and ameliorated cognitive deficits in multiple mouse models of AD.