PROJECT SUMMARY Alzheimer’s disease (AD) is one of the leading causes of death among the elderly community in the United States. The socio-economic burden of the disease is steeply escalating as the number of AD patients is projected to nearly triple to 14 million by 2060. Memory loss is a core clinical phenotype results from irreversible damage of neuronal circuits in the brain. Although advances in science have made remarkable strides in understanding the disease, the currently approved drugs focus primarily on alleviating symptoms, not stalling disease progression. Neuroinflammation due to the aggregation and inappropriate clearance of fibril amyloid-beta (fAβ) by glial cells is a hallmark of AD. Glial cells including microglia and astrocytes communicate through signaling pathways and an ensemble of receptors including scavenger receptors (SRs). In AD, the recognition of fAβ by SRs triggers glial activation, attenuates glial clearance of fAβ and exacerbates neuroinflammation. Our labs have advanced a library of synthetic amphiphilic macromolecule (AMs)-based nanoparticles (NPs) that can be targeted to ensemble SR receptors. Our preliminary data show that SR-specific AM-NPs counteract the fAβ-mediated inflammatory microglial activation. In line with this, the internalization of fAβ through SRs is blocked by AM-NPs in microglia. Furthermore, AM-NPs arrest the in vitro formation of fAβ from monomers. Interestingly, our AM-NPs stimulate fAβ lysosomal clearance in microglial. Finally, our AM-NPs prevent the neurotoxic effect of fAβ-induced microglial inflammatory cytokines. Given these findings, we hypothesize that the utilization of SR-selective NPs is a neuroprotective multimodal approach to interrupt fAβ-SRs complex formation and arrest inflammatory cascade of glial communication. This hypothesis will be addressed in the following specific aims: (1) to elucidate the role of SR-targeted NPs in the amelioration of fAβ-mediated pathological glial communications; and (2) to evaluate the longer-term neuroprotective effects of SR-specific AM-NPs within an AD pathological model based on 3D multicellular human organoid cultures. In summary, this exploratory study seeks to develop an innovative nanotechnology to abrogate the neuroinflammatory crosstalk that exacerbates AD progression using state-of-the-art technologies of nanoparticles, stem cells, and brain-like mimetic human organoids.