Chrysanthemum Morifolium– Derived Nanovesicles Reduce Lactate‐Associated Histone Lactylation and Modulate Microglia‐Mediated Neuroinflammation in Sepsis‐Associated Encephalopathy

Sepsis-associated encephalopathy (SAE)-a complication of the central nervous system in patients with sepsis-markedly diminishes cognitive functions and is linked to hippocampal neuritis-induced injury. Plant exosome-like nanovesicles can transport proteins, lipids, and molecular compounds between neural cells and the periphery, thereby modulating target cells. This study examined the therapeutic potential of Chrysanthemum morifolium-derived exosome-like nanovesicles (CRELNVs) in an animal model of lipopolysaccharide-induced SAE, revealing their ability to effectively cross the blood-brain barrier, be internalized by microglia, and alleviate nerve injury and memory impairment by reducing lactate levels in microglia at the hippocampus. CRELNVs decreased lactylation levels in microglia, thus promoting the conversion of microglial cells from the detrimental M1 metabolic phenotype to the protective M2 one. Mechanistically, our finding suggest CRELNVs reduced proinflammatory cytokine release is associated with the inhibition of NF-κB activation. Thus, CRELNVs were concluded to exert their protective effects by modulating the H3K18la/NF-κB axis and regulate microglia-mediated neuroinflammation by responding to the hippocampal neuritis-induced injury in SAE.