Communications Among Neurocytes in Parkinson's Disease Regulated by Differential Metabolism and Blood‐Brain Barrier Traversing of Chiral Gold Cluster‐MOF Integrated Nanoparticles

This study have previously reported that ZIF-based chiral nanomedicines achieve Parkinson's disease (PD) therapy through differential metabolism and relief of neuroinflammation. However, lack of overall chirality and anti-inflammatory capacity of nanomedicines limit the further effective solution to the nanobiological effects research in PD. Here, it dexterously loaded chiral gold nanoclusters (AuNCs) onto the inner and outer surfaces of ZIF to achieve the purpose of simultaneously improving the overall chirality and anti-inflammatory activity of the composite nanoparticles (NPs). There are significant differences in the composition of protein corona between different chiral NPs, which elucidates the mechanism of chiral-mediated discrepancies in metabolism and the blood-brain barrier (BBB) traversing. Multi-omics and biochemical techniques further reveal that chiral NPs interfere with the chemokine axis (CX3CL1/CX3CR1)-NF-κB-NLRP3 and PI3K-AKT signaling pathways, regulate communications between neurons, neural stem cells and microglia ("the three-body problem"), and induce anti-inflammatory efficacy of microglia mitochondrial energy metabolic reprogramming in PD. The research uncovers the biodistribution, metabolic variances, and therapeutic mechanism of chiral NPs, providing deep insights into the nanobiological effects of chiral anti-inflammatory nanomedicines in PD therapy for future clinical transformation.