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Small extracellular vesicles (sEVs) derived from bone marrow mesenchymal stem cells (BMSCs) have been suggested to have satisfactory therapeutic effects on IS by the delivery of their packed microRNA (miRNA). However, systematically administered na\u00efve sEVs are difficult to cross the blood\u2010brain barrier (BBB) and enter the brain parenchyma; also, the low abundance of sEVs cargo miRNAs restricts the possibility of maximising their regulatory functions. Hence, the brain targeting modification and miRNA delivery strategy are crucial for the optimisation of BMSC\u2010sEVs therapeutic effects. In this study, based on sEVs miRNA\u2010seq and analysis of the RNA\u2010seq datasets for ischaemic stroke patients\u2019 samples in the GEO database, we identified that miR\u201021 sharply drops in the ischaemic brain. By the bioengineered BMSCs with RVG\u2010Lamp2b peptide and miR\u201021\u20105p overexpression plasmid, RVG\u2010miR21\u2010sEVs were successfully developed. After characterisation of RVG\u2010miR21\u2010sEVs, it showed that RVG\u2010modified sEVs had a high affinity to neurons, and the administration of RVG\u2010miR21\u2010sEVs displayed superior neurological functional rehabilitation and cerebral infarction reduction in the mouse transient middle cerebral artery occlusion (tMCAo) model. Additionally, RVG\u2010miR21\u2010sEVs treatment suppressed neuron autophagy, mitochondria dysfunction and apoptosis after oxygen\u2010glucose deprivation\/re\u2010oxygenation (OGD\/R) insult. Furthermore, by using dual\u2010luciferase reporter assay, FISH technique, and miR\u201021 inhibitor and mimics transfection, we validated that the target of miR\u201021 is PTEN, and the mechanism investigation showed that miR\u201021 targets the PTEN\/Akt\/mTOR pathway to antagonise neuronal injury due to excessive autophagy.<\/jats:p>","DOI":"10.1002\/jev2.70295","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T06:48:25Z","timestamp":1778050105000},"source":"Crossref","is-referenced-by-count":3,"title":["RVG\u2010Modified BMSCs\u2010Derived Small Extracellular Vesicles Loaded With miR\u201021 Alleviate Neuronal Injury Resulted From Excessive Autophagy via Targeting PTEN\/Akt\/mTOR Pathway After Cerebral Ischaemia"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5791-9371","authenticated-orcid":false,"given":"Yiyang","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Mechanism and 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