Intervention in chronically activated microglia-mediated neuroinflammation is a novel approach to treat Alzheimer's disease (AD). The low permeability of the blood‒brain barrier (BBB) and non-selective distribution in the brain severely restrict AD drugs' disease-modifying efficacy. Here, an immunosuppressant TREM2-lowing antisense oligonucleotides (ASOs) and resveratrol co-loaded cationic liposome is developed as an immune reprogramming nanomodulator modified by acid-cleavable BBB-targeting peptide and microglia-targeting peptide (Res@TcMNP/ASO) for AD management. Res@TcMNP/ASO can enter brain endothelial cells via D-T7 peptides. Then D-T7 undergoes an acid-responsive cleavage, facilitating the escape of Res@MNP/ASO from endo/lysosomes to cross the BBB. The detached Res@MNP/ASO specifically targets M1-phenotype microglia via exposed MG1 peptides to prompt the simultaneous delivery of two drugs into activated microglia. This nanomodulator can not only restore the immune function of microglia through TREM2-lowing ASO but also mitigate the immune stimulation to microglia caused by reactive oxygen species (ROS) through resveratrol, thereby synergistically inhibiting the chronic activation of microglia to alleviate neuroinflammation in AD. Our results indicate that this combination treatment can achieve significant behavioral and cognitive improvements in late APP/PS1 mice.

OBJECTIVE:To identify lipid metabolites of endophytic fungus Aspergillus terreus from Polygonum capitatum, and to investigate their anti-multidrug resistant bacteria and anti-inflammatory effects. METHODS:GC-MS was used to analyze and identify lipid metabolites of A. terreus. MIC of lipid metabolites and main composition to 10 strains of multidrug resistant bacteria (Klebsiella pneumoniae,Proteus common,Staphylococcus epidermidis,Escherichia coli,Staphylococcus aureus,Enterobacter cloacae,Pseudomonas aeruginosa,Proteus mirabilis,Enterococcus faecium and Acinetobacter baumanii) were determined by 96-well plate microdilution method. The spread plate method was used to determine MBC of samples to bacteria. LPS-induced RAW264.7 inflammatory model was used to investigate the effects of different mass concentrations(50,100,200 μg/mL)of lipid metabolites on the release of NO and TNF-α after treated for 24 h. RESULTS:A total of 13 compounds were identified in lipid metabolites of A. terreus,among which palmitic acid,stearic acid,linoleic acid and oleic acid were main components,and relative percentages of them were 29.35％,10.87％,21.94％,34.85％. The lipid metabolites displayed anti-bacterial activity against E. coli and K. pneumonia with MICs of 12.5 mg/mL and 50 mg/mL,MBC of 25 mg/mL and 100 mg/mL,respectively. The main 4 compositions could inhibit the growth of E. coli,with MIC of 0.5-1 mg/mL,among which palmitic acid showed significant antibacterial activity,especially to E. faecium(MIC of 0.25 mg/mL). 50,100 μg/mL lipid metabolites could signifiantly inhibit the release of inflammatory factor of NO and TNF-α in RAW264.7 in vitro. CONCLUSIONS:The lipid metabolites of endophytic fungus A. terreus from P. capitatum show anti- multi-drug resistant bacteria and anti-inflammatory effects.