Portulaca oleracea L.-Derived Exosome-Like Nanoparticles for Promoting Cutaneous Wound Healing

Abstract Plant-derived extracellular vesicles are emerging as potent cell-free nanotherapies. Portulaca oleracea L.-derived exosome-like nanoparticles (PELNs) exhibit significant anti-inflammatory properties and potential for modulating the regenerative microenvironment. However, their mechanisms in cutaneous wound healing are not fully elucidated. Herein, we isolated PELNs via ultracentrifugation and investigated their roles in macrophage polarization, re-epithelialization, and angiogenesis. PELNs markedly inhibited LPS-induced pro-inflammatory M1 macrophage polarization and attenuated IL-1β and IL-6 expression, facilitating a rapid in vivo transition from the inflammatory to the remodeling phase. Additionally, PELNs demonstrated robust pro-angiogenic and proliferative activity, enhancing endothelial and epidermal cell proliferation, migration, and tube formation. In vivo results confirmed accelerated wound closure, reduced inflammation, increased neovascularization, and organized collagen deposition in PELNs-treated groups. Mechanistically, PELNs activated the Wnt/β-catenin signaling pathway in both HaCaT and HUVECs by promoting β-catenin nuclear translocation and significantly upregulating downstream target genes. Collectively, PELNs promote skin repair by suppressing M1 polarization to optimize the immune microenvironment and synergistically activating Wnt/β-catenin signaling pathways to drive re-epithelialization and angiogenesis, providing a theoretical basis for their clinical application in inflammatory wounds.