Low‑intensity pulsed ultrasound accelerates diabetic wound healing by ADSC‑derived exosomes via promoting the uptake of exosomes and enhancing angiogenesis

Diabetic wounds remain a great challenge for clinicians globally as a lack of effective radical treatment often results in poor prognosis. Exosomes derived from adipose‑derived stem cells (ADSC‑Exos) have been explored as an appealing nanodrug delivery system in the treatment of diabetic wounds. However, the short half‑life and low utilization efficiency of exosomes limit their therapeutic effects. Low‑intensity pulsed ultrasound (LIPUS) provides a non‑invasive mechanical stimulus to cells and exerts a number of biological effects such as cavitation and thermal effects. In the present study, whether LIPUS could enhance ADSC‑Exo‑mediated diabetic wound repair was investigated and its possible mechanism of action was explored. After isolation and characterization, ADSC‑Exos were injected into mice with diabetic wounds, then the mice were exposed to LIPUS irradiation. The control mice were subcutaneously injected with PBS. Wound healing assays, laser Doppler perfusion, Masson's staining and angiogenesis assays were used to assess treatment efficiency. Then, ADSC‑Exos were cocultured with human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation of HUVECs were assessed. Moreover, the cellular uptake of ADSC‑Exos in vitro and in vivo was assessed to explore the synergistic mechanisms underlying the effects of LIPUS. The in vivo results demonstrated that LIPUS increased the uptake of exosomes and prolonged the residence of exosomes in the wound area, thus enhancing angiogenesis and accelerating wound repair in diabetic mice. The in vitro results further confirmed that LIPUS enhanced the uptake efficiency of ADSC‑Exos by 10.93‑fold and significantly increased the proliferation, migration and tubular formation of HUVECs. Therefore, the present study indicates that LIPUS is a promising strategy to improve the therapeutic effects of ADSC‑Exos in diabetic wounds by promoting the cellular uptake of exosomes and enhancing angiogenesis.