Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor for cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates cognitive impairment via anti‐oxidative stress and anti‐inflammation properties; however, the underlying mechanisms linking riboflavin metabolism and microglial function in cognitive impairment remain unclear. Here, it is demonstrated that riboflavin kinase (RFK), a critical enzyme in riboflavin metabolism, is specifically expressed in microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression via regulation of lysine‐specific methyltransferase 2B (KMT2B). FMN supplementation attenuated the pro‐inflammatory TNFR1/NF‐κB signaling pathway, and this effect is abolished by KMT2B overexpression. To improve the limited anti‐inflammatory efficiency of free FMN, a biomimetic microglial nanoparticle strategy (designated as MNPs@FMN) is established, which penetrated the blood brain barrier with enhanced microglial‐targeted delivery efficiency. Notably, MNPs@FMN ameliorated cognitive impairment and dysfunctional synaptic plasticity in a lipopolysaccharide‐induced inflammatory mouse model and in a 5xFAD mouse model of Alzheimer's disease. Taken together, biomimetic microglial delivery of FMN may serve as a potential therapeutic approach for inflammation‐dependent cognitive decline. A biomimetic microglial nanoparticle system (MNPs@FMN) is established for precise microglial delivery of flavin mononucleotide (FMN) to ameliorate cognitive impairment and restore synaptic plasticity in inflammation‐based cognitive decline mouse models. Mechanistically, MNPs@FMN alleviated pro‐inflammatory response by inhibiting the TNFR1/NF‐κB signaling pathway, for which this neuroprotection may be involved in the regulation of microglial expressed riboflavin kinase (RFK) via KMT2B.