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Epithelial regeneration is an essential wound healing process, and recent work suggests that different types of exosomes (Exos) can improve wound repair outcomes by promoting such epithelial regeneration. Platelet-rich plasma (PRP) is known to facilitate enhanced wound healing, yet the mechanisms underlying its activity are poorly understood. To explore these mechanisms, we first isolated PRP-derived Exos (PRP-Exos). Using immortalized keratinocytes (HaCaT cells) treated with PBS, PRP, or PRP-Exos, we conducted a series of  in vitro  Cell Counting Kit-8 (CCK-8), EdU, scratch wound, and transwell assays. We then established a wound defect model  in vivo  in mice and assessed differences in the mRNA expression within these wounds to better understand the basis for PRP-mediated wound healing. The functions of PRP-Exos and USP15 in the context of wound healing were then confirmed through additional  in vitro  and  in vivo  experiments. We found that PRP-Exos effectively promoted the  in vitro  proliferation, migration, and wound healing activity of HaCaT cells. USP15 was further identified as a key mediator through which these PRP-Exos were able to promote tissue repair both  in vitro  and  in vivo . At a mechanistic level, USP15 enhanced the functional properties of HaCaT cells by promoting EIF4A1 deubiquitination. Thus, PRP-Exos and USP15 represent promising tools that can promote wound healing via enhancing epithelial regeneration.

Platelet-Rich Plasma-Derived Exosomal USP15 Promotes Cutaneous Wound Healing via Deubiquitinating EIF4A1