Neural inflammatory response is a crucial pathological change in intracerebral hemorrhage (ICH) which accelerates the formation of perihematomal edema and aggravates neural cell death. Although surgical and drug treatments for ICH have advanced rapidly in recent years, therapeutic strategies that target and control neuroinflammation are still limited. Exosomes are important carriers for information transfer among cells. They have also been regarded as a promising therapeutic tool in translational medicine, with low immunogenicity, high penetration through the blood-brain barrier, and ease of modification. In our previous research, we have found that exogenous administration of miRNA-124-overexpressed microglial exosomes (Exo-124) are effective in improving post-injury cognitive impairment. From this, we evaluated the potential therapeutic effects of miRNA-124-enriched microglial exosomes on the ICH mice in the present study. We found that the gene-edited exosomes could attenuate neuro-deficits and brain edema, improve blood–brain barrier integrity, and reduce neural cell death. Moreover, the protective effect of Exo-124 was abolished in mice depleted of Gr-1⁺ myeloid cells. It suggested that the exosomes exerted their functions by limiting the infiltration of leukocyte into the brain, thus controlling neuroinflammation following the onset of ICH. In conclusion, our findings provided a promising therapeutic strategy for improving neuroinflammation in ICH. It also opens a new avenue for intranasal delivery of exosome therapy using miRNA-edited microglial exosomes.

Background: Ischemic stroke (IS) and aging share similar pathophysiological features, including vascular dysfunction, inflammatory responses, and oxidative stress. However, the underlying molecular mechanisms remain unclear. This study aimed to identify key shared drive genes between IS and aging through integrated multi-omics analysis and machine learning approaches, and to explore their diagnostic and therapeutic potential. Methods: Based on the GSE22255 and GSE58294 datasets, differentially expressed genes (DEGs) associated with IS were screened using differential expression analysis and weighted gene co-expression network analysis (WGCNA). The overlapping genes between IS-related DEGs and aging-related genes (ARGs) were identified as aging-related DEGs (ARDEGs). Further refinement of core genes was performed through Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI) network construction, and machine learning algorithms (LASSO regression and support vector machine [SVM]). Immune cell infiltration was evaluated using CIBERSORT, and gene expression patterns were validated via the DISCO single-cell database. Finally, molecular docking and drug database screening were employed to predict potential therapeutic targets. Results: A total of 279 IS-related DEGs were identified, among which 29 showed significant overlap with ARGs (ARDEGs). WGCNA revealed that the MEcyan module exhibited a strong negative correlation with IS phenotypes (r = -0.63). Machine learning algorithms identified JUP, UQCRC1, and MRPL41 as core potential diagnostic biomarkers, with area under the curve (AUC) values all exceeding 0.7. Immune infiltration analysis demonstrated a significant increase in M1 macrophages and neutrophils, along with a reduction in CD8+ T cells in IS patients. Single-cell data confirmed the specific expression of these core genes in neurons and immune cells. Molecular docking suggested that the herbicide atrazine may target these genes (binding energy < -5.7 kcal/mol), while hsa-miR-30c-5p was predicted to regulate JUP and UQCRC1. Conclusion: This study elucidates key shared genes and immune microenvironment features between IS and aging, proposing JUP, UQCRC1, and MRPL41 as potential diagnostic biomarkers. Furthermore, atrazine was identified in silicoas a potential interacting molecule, suggesting the druggability of these target proteins and providing a starting point for future drug discovery efforts in IS.

Aging leads to neurodegenerative diseases, such as cognitive decline, which are induced by persistent chronic low‐grade inflammation in the brain driven by microglial activation. However, whether and how brain‐derived exosomes from aged mice (A‐exo) induce a pro‐inflammatory state and cellular senescence in microglia within the aging brain is poorly understood. Here, we report that brain‐derived exosomes from aged mice (A‐exo) cause cognitive decline in normal young mice, inducing microglial overactivation, lipid droplet accumulation, and senescence‐associated secretory phenotype (SASP) secretion. This abnormal microglial activity arises from the elevated expression of PTGDS in A‐exo due to mouse aging, resulting in increased central and peripheral D‐prostanoid receptor 1 (DP1) ligand PGD2 levels, which subsequently leads to sustained DP1 signaling activation. Consequently, this process promotes myeloid cell infiltration, cellular senescence, and cognitive decline by generating a senescent, pro‐inflammatory microglial phenotype. Blocking the DP1 receptor ameliorates A‐exo‐mediated microglial overactivation, myeloid cell infiltration, and cellular senescence. Strikingly, DP1 receptor blockade improves cellular senescence, neuroinflammation, and cognitive decline in aged mice. Our findings reveal a systemic mechanism underlying the sustained activation of microglia following brain aging, paving the way for improving chronic neuroinflammation, cellular senescence, and cognitive decline associated with aging.