Macrophage heterogeneity regulation by small extracellular vesicles from adipose-derived stem cells: A promising approach for treating chronic prostatitis/pelvic pain syndrome

chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an intractable aseptic disease. Modulating the transition of macrophages from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype offers an attractive therapeutic approach. Recently, small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) reportedly have potent modulatory abilities, however, their applications are limited by suboptimal targeting. Our group hypothesized that surface modification of sEVs derived from ADSCs are useful for the management of CP/CPPS by promoting M1/M2 macrophage phenotypic transformation. In this study, a novel nanomaterial (CD86-sEVs) is designed for CP/CPPS treatment using click chemistry, a bioconjugation technique enabling robust covalent linkages. The results of immunofluorescence staining, western blot and ELISA confirmed that azide-modified CD86 antibody was successfully conjugated onto the sEVs surface. In vitro, CD86-sEVs significantly accelerated M1 macrophage polarization to M2 and upregulated anti-inflammatory factors. In vivo, CD86-sEVs targeted the prostatic lesion region, alleviated chronic pelvic pain, and inhibited inflammation by promoting M1/M2 phenotype shift. Furthermore, miRNA array analysis identified specific miRNAs (miR-26a, miR-147, miR-17, miR-21, miR-182, miR-451a) within CD86-sEVs that likely contributed to these observed effects. In sum, this study presents a novel paradigm for the treatment of CP/CPPS.