Background Bone marrow-derived mesenchymal stem cells (BMSCs)-derived extracellular vesicles (EVs) have shown potent anti-inflammatory function in various pathological conditions, such as osteoarthritis and neurodegenerative diseases. Since the number of EVs naturally secreted by cells is finite and they usually bear specific repertoires of bioactive molecules to perform manifold cell–cell communication, but not one particular therapeutic function as expected, their practical application is still limited. Strategies are needed to increase the production of EVs and enhance their therapeutic function. Recent studies have suggested that low-intensity pulsed ultrasound (LIPUS) is a promising non-invasive method to increase the secretion of EVs and promote their anti-inflammatory effects. However, the effect of LIPUS stimulation of BMSCs on EVs derived from the cells remains unclear. The objective of this study was to investigate whether LIPUS stimulation on BMSCs could increase the secretion of EVs and enhance their anti-inflammatory effects. Methods BMSCs were exposed to LIPUS (300 mW/cm2) for 15 min and EVs were isolated by ultracentrifugation. Anti-inflammatory effects of EVs were investigated on RAW264.7 cells in vitro and in the allogeneic skin transplantation model. Small RNA-seq was utilized to identify components difference in EVs with/without LIPUS irradiation. Results In this study, we found that LIPUS stimulation could lead to a 3.66-fold increase in the EVs release from BMSCs. Moreover, both in vitro and in vivo experimental results suggested that EVs secreted from LIPUS-treated BMSCs (LIPUS-EVs) possessed stronger anti-inflammatory function than EVs secreted from BMSCs without LIPUS stimulation (C-EVs). RNA-seq analysis revealed that miR-328-5p and miR-487b-3p were significantly up-regulated in LIPUS-EVs compare with C-EVs. The suppression of MAPK signaling pathway by these two up-regulated miRNAs could be the potential mechanism of strengthened anti-inflammatory effects of LIPUS-EVs. Conclusion LIPUS stimulation on BMSCs could significantly increase the secretion of EVs. Moreover, EVs generated from LIPUS-treated BMSCs possessed much stronger anti-inflammatory function than C-EVs. Therefore, LIPUS could be a promising non-invasive strategy to promote the production of EVs from BMSCs and augment their anti-inflammatory effects.

As macrophage infiltration is significantly related to the progression of inflammatory bowel disease (IBD), monitoring the macrophages is a valuable strategy for IBD diagnosis. However, owing to the harsh physiological environment of the gastrointestinal tract and enzymatic degradation, the development of orally administrable imaging probes for tracking macrophages remains a considerable challenge. Accordingly, herein, an orally administrable aggregation‐induced emission biomimetic probe (HBTTPIP/β‐glucan particles [GPs]) is developed for tracing macrophages; HBTTPIP/GPs can diagnose and alleviate dextran sulfate sodium (DSS)‐induced colonic inflammation and self‐report the treatment efficiency. The fluorophore HBTTPIP can effectively aggregate in GPs, restricting intramolecular rotation and activating the fluorescence of HBTTPIP. After being orally administrated, HBTTPIP/GPs are phagocytosed by intestinal macrophages, which then migrate to colonic lesions, enabling non‐invasive monitoring of the severity of IBD via in vivo fluorescence imaging. Notably, oral HBTTPIP/GPs ameliorate DSS‐induced IBD by inhibiting the expressions of pro‐inflammatory factors and improving colonic mucosal barrier function. Furthermore, these HBTTPIP/GPs realize self‐feedback of the therapeutic effects of GPs on DSS‐induced colitis. The oral biomimetic probe HBTTPIP/GPs reported herein provide a novel theranostic platform for IBD, integrating non‐invasive diagnosis of IBD in situ and the corresponding treatment.