Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia
ABSTRACT Stroke remains the leading cause of neurological mortality and disability worldwide, with post‐stroke inflammation significantly hindering neural repair. Despite its critical impact, mechanism‐based therapeutic strategies are scarce. In this study, we uncovered a critically important yet pr...
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Wiley
2025-06-01
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| Series: | Exploration |
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| Online Access: | https://doi.org/10.1002/EXP.20240349 |
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| author | Jialei Yang Shipo Wu Miao He |
| author_facet | Jialei Yang Shipo Wu Miao He |
| author_sort | Jialei Yang |
| collection | DOAJ |
| description | ABSTRACT Stroke remains the leading cause of neurological mortality and disability worldwide, with post‐stroke inflammation significantly hindering neural repair. Despite its critical impact, mechanism‐based therapeutic strategies are scarce. In this study, we uncovered a critically important yet previously unexamined cell population, p21+CD86+ microglia, which accumulated in ischemic region. Unexpectedly, we discovered that p21 interacted with C/EBPβ, driving C/EBPβ‐dependent transcription and upregulating key pro‐inflammatory factors such as Il6, Il1β, Cxcl2, and Cxcl10. To specifically target and eliminate these pathogenic p21+CD86+ microglia, we engineered exosomes with a peptide that selectively binds CD86+ microglia and loaded them with the senolytic Quercetin. Furthermore, we developed an optimized, stable Que@micro‐Exo therapeutic formulation. Systemic administration of Que@micro‐Exo robustly reduced p21+CD86+ microglia and suppressed their pro‐inflammatory phenotype. Notably, functional analyses revealed that Que@micro‐Exo treatment mitigated blood‐brain barrier disruption, promoted beneficial microglial polarization, decreased neutrophil infiltration, and significantly enhanced functional recovery following cerebral ischemia, all with a favorable safety profile. Our preclinical findings lay the foundation for targeting p21+CD86+ microglia as a novel therapeutic strategy, highlighting the potential of exosome‐based senolytic anti‐inflammatory therapy for stroke and other central nervous system disorders. |
| format | Article |
| id | doaj-art-bf0f6b7a25d44778a7c7d8d542aa65f5 |
| institution | OA Journals |
| issn | 2766-8509 2766-2098 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Exploration |
| spelling | doaj-art-bf0f6b7a25d44778a7c7d8d542aa65f52025-08-20T02:36:23ZengWileyExploration2766-85092766-20982025-06-0153n/an/a10.1002/EXP.20240349Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ MicrogliaJialei Yang0Shipo Wu1Miao He2Department of Neurology, China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital, Capital Medical University Beijing ChinaLaboratory of Advanced Biotechnology Beijing Institute of Biotechnology Beijing ChinaDepartment of Neurology, China National Clinical Research Center for Neurological Diseases Beijing Tiantan Hospital, Capital Medical University Beijing ChinaABSTRACT Stroke remains the leading cause of neurological mortality and disability worldwide, with post‐stroke inflammation significantly hindering neural repair. Despite its critical impact, mechanism‐based therapeutic strategies are scarce. In this study, we uncovered a critically important yet previously unexamined cell population, p21+CD86+ microglia, which accumulated in ischemic region. Unexpectedly, we discovered that p21 interacted with C/EBPβ, driving C/EBPβ‐dependent transcription and upregulating key pro‐inflammatory factors such as Il6, Il1β, Cxcl2, and Cxcl10. To specifically target and eliminate these pathogenic p21+CD86+ microglia, we engineered exosomes with a peptide that selectively binds CD86+ microglia and loaded them with the senolytic Quercetin. Furthermore, we developed an optimized, stable Que@micro‐Exo therapeutic formulation. Systemic administration of Que@micro‐Exo robustly reduced p21+CD86+ microglia and suppressed their pro‐inflammatory phenotype. Notably, functional analyses revealed that Que@micro‐Exo treatment mitigated blood‐brain barrier disruption, promoted beneficial microglial polarization, decreased neutrophil infiltration, and significantly enhanced functional recovery following cerebral ischemia, all with a favorable safety profile. Our preclinical findings lay the foundation for targeting p21+CD86+ microglia as a novel therapeutic strategy, highlighting the potential of exosome‐based senolytic anti‐inflammatory therapy for stroke and other central nervous system disorders.https://doi.org/10.1002/EXP.20240349engineered exosomesextracellular vesiclesischemic strokemicrogliasenescencetargeted delivery |
| spellingShingle | Jialei Yang Shipo Wu Miao He Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia Exploration engineered exosomes extracellular vesicles ischemic stroke microglia senescence targeted delivery |
| title | Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia |
| title_full | Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia |
| title_fullStr | Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia |
| title_full_unstemmed | Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia |
| title_short | Engineered Exosome‐Based Senolytic Therapy Alleviates Stroke by Targeting p21+CD86+ Microglia |
| title_sort | engineered exosome based senolytic therapy alleviates stroke by targeting p21 cd86 microglia |
| topic | engineered exosomes extracellular vesicles ischemic stroke microglia senescence targeted delivery |
| url | https://doi.org/10.1002/EXP.20240349 |
| work_keys_str_mv | AT jialeiyang engineeredexosomebasedsenolytictherapyalleviatesstrokebytargetingp21cd86microglia AT shipowu engineeredexosomebasedsenolytictherapyalleviatesstrokebytargetingp21cd86microglia AT miaohe engineeredexosomebasedsenolytictherapyalleviatesstrokebytargetingp21cd86microglia |