Mechanistic Insights and Therapeutic Potential of Plant-Derived Exosome-Like Nanovesicles in Skin Tissue Regeneration

The integrity of the skin barrier is paramount for human physiological homeostasis. Recently, plant-derived exosome-like nanovesicles (PENs) lipid bilayer nanostructures inherently enriched with diverse natural bioactive cargos have emerged as transformative nanotherapeutic platforms. Compared to conventional mammalian and microbial-derived extracellular vesicles (EVs), PENs offer distinct clinical translation advantages. These include scalable and sustainable production, exceptional biosafety, and remarkably low immunogenicity, providing a highly biocompatible alternative for regenerative medicine. This review systematically integrates the multifactorial roles of PENs across the full continuum of skin wound healing. By mediating dynamic cross-kingdom signal transduction, PENs orchestrate a seamless regenerative cascade. Initially, they efficiently mitigate inflammation by tuning macrophage polarization, suppressing inflammasome activation, and alleviating oxidative stress to restore a permissive tissue microenvironment. Furthermore, PENs drive robust angiogenesis by upregulating essential proangiogenic markers and inhibiting local ferroptosis. Concurrently, they promote peripheral neural repair via PI3K/ERK pathway activation, facilitating vital neurovascular crosstalk that ultimately stabilizes nascent microvascular networks. Beyond early wound closure, PENs crucially support the high quality structural reconstruction and functional homeostasis of skin appendages specifically hair follicles, sebaceous glands, and sweat glands through modulating key cascades such as the Wnt/β-catenin pathway. Additionally, we summarize standard isolation and characterization technologies, highlighting PENs' unique functional attributes. By exploring advanced bioengineering prospects, this review establishes a comprehensive mechanistic framework for developing PENs as safe and precise nanomedicines for complete skin functional reconstruction.