Cerebral organoid exosomes reversed behavioral deficits by repressing NLRP3-mediated neuroinflammation in stress models

Depression, a highly prevalent neuropsychiatric disorder, involves neuroinflammation in its pathophysiology. Exosomes have emerged as a promising strategy for modulating neuroinflammation, however, the potential of cerebral organoid (CO)-derived exosomes (OExos) in regulating neuroinflammation and their efficacy in treating depression remain unexplored. Using induced pluripotent stem cell-derived cerebral organoids containing neural progenitors, neurons, and glia, we demonstrated through proteomics that OExo modulate depression-associated inflammatory pathways by coordinately regulating NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome cascade. <i>In vitro</i>, OExo suppressed lipopolysaccharide-induced NLRP3 inflammasome activation and microglial polarization, reducing neurotoxic astrocyte activation and neuronal synaptic loss. In chronic mild stress (CMS) models, intranasal OExo delivery attenuated hippocampal NLRP3 activation in microglia, decreased pro-inflammatory cytokines, and mitigated neurotoxic astrogliosis and synaptic protein loss. Consequently, OExo treatment significantly alleviated CMS-induced anxiety, anhedonia, and depressive-like behaviors. These findings demonstrate OExo effectively ameliorate NLRP3-mediated neuroinflammation in depression models, supporting their therapeutic potential.