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

Abstract

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.

Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

“…It decreased CypD expression by 44.9%, inhibited Drp1 expression, and enhanced OPA1 expression to halt the mitochondrial dysfunction cascade. [226] Regulation of inflammation-related pathways (including upward and downward regulation) [227,228] can also enhance mitochondrial protection by cutting off the vicious circle between inflammation and other pathological phenomena such as oxidative stress. [229,230] Ac2-26, an Annexin 1(ANXA1) derived peptide, can prevent neutrophils from infiltrating and adhering by acting on the lipotoxin A4 receptor (ALXR/FPRL1) on the cell surface to repress inflammation.…”

“…Cognitive Impairment MNPs@FMN [ 228] --106 -FMN Friedrich's ataxia Cur@SF NPs [ 276] --≈150 -Curcumin…”

Nanomedicines for Alzheimer's disease: Therapies based on pathological mechanisms

“…Reproduced from Ref. [124] with permission. (I) Mode of action and side effects (neuroinflammation) of lipid nanoparticles (LNP)‐Aβ, and the proposed therapeutic mechanisms of LNP‐R/Aβ for the treatment of Alzheimer's disease (AD).…”

“…At present, only one report has suggested that the rapid capture of neutrophils by neutrophil extracellular traps at the inflammatory lesion site results in rapid degradation and the release of loaded drugs [181] . Biomimetic drug delivery systems based on macrophage [123] and microglia [124] membranes can help the drug reach the target lesion and become endocytosed by microglia, but it is still unclear how the drug is released. One recent study showed that a biomimetic carrier based on osteoclast membranes can circumvent lysosomes and achieve drug release through membrane fusion, and the absorbed drug can also be transported between cells via exosomes [182] .…”

“…A similar phenomenon was also observed in astrocytes (Figure 6G,H). [124] In addition, recent studies have revealed that mitogen‐activated protein kinase (MAPK), IκBα, triggering receptor expressed on myeloid cells 2 (TREM2), and other signaling factors can also regulate NF‐κB. The former two can be targeted by small‐molecule drugs such as oxytocin [143] and rhein, [185] whereas TREM2 can mainly be targeted by nucleic acid drugs, such as TREM2‐encoding plasmid [92] and siRNA [186] .…”