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Figure 4. EV pre-treatment for enhanced therapeutic efficacy. (A) Environmental Preconditioning: Hypoxic preconditioning of ADSCs enriches circ-Epc1, promoting microglial polarization toward the anti-inflammatory M2 phenotype; hypoxic preconditioning of BMSCs enhances cell migration and tissue repair; heat shock treatment of neural stem cells increases anti-apoptotic and DNA repair capabilities, thereby augmenting the antioxidant capacity of the secreted EVs; (B) Pharmacological Preconditioning: Treatment of microglia with lovastatin promotes insulin-degrading enzyme secretion via their EVs; treatment of mesenchymal stem cells with Salvia miltiorrhiza extract upregulates miR-27a-5p, thereby enhancing Aβ degradation and tissue repair capabilities; (C) Inflammatory Factor Preconditioning: Stimulation of DFSCs with LPS downregulates miR-184 and activates the PPARα-Akt and JNK pathways, suppressing oxidative stress and promoting regeneration. ADSC: Adipose-derived stem cell; circ-Epc1: circular RNA enhancer of polycomb homolog 1; TREM2: triggering receptor expressed on myeloid cells-2; BMSC: bone marrow mesenchymal stem cell; Aβ: amyloid-beta; DFSC: dental follicle stem cell; LPS: lipopolysaccharide; PPARα: peroxisome proliferator-activated receptor alpha; EV: extracellular vesicle; JNK: c-Jun N-terminal kinase. Created in BioRender. yinghan, h. (2025) https://BioRender.com/p093jkc