紫外线 (UV) 辐射是皮肤老化的主要外在因素，可导致皮肤光老化、光化性角化病 (AK)，甚至鳞状细胞癌 (SCC)。目前，间充质基质细胞衍生的小细胞外囊泡（MSC-sEV）在皮肤伤口愈合中的有益作用已被广泛报道，但光老化领域仍有待探索。我们的研究结果表明，人脐带间充质干细胞衍生的 sEV（hucMSC-sEV）干预可以有效缓解体内和体外皮肤光老化表型，包括改善紫外线引起的皮肤组织病理学变化，抑制真皮成纤维细胞的氧化应激和胶原蛋白降解。 DF）。从机制上讲，hucMSC-sEVs 预处理逆转了 UVA 诱导的 DF 中妊娠区蛋白 (PZP) 的下调，并通过抑制基质金属蛋白酶-1 (MMP-1) 表达和减少 DNA 损伤来实现光保护。临床上观察到AK和SCC原位样本中PZP显着下降，而侵袭性SCC样本中PZP出现反弹。总的来说，我们的研究结果揭示了 hucMSC-sEVs 在调节 PZP 对抗光老化方面的有效作用，并为 hucMSC-sEVs 作为有效皮肤光保护剂的潜在开发提供了新的临床前证据。© 作者 2024。出版者牛津大学出版社。

Ultraviolet (UV) radiation is the primary extrinsic factor in skin aging, contributing to skin photoaging, actinic keratosis (AK), and even squamous cell carcinoma (SCC). Currently, the beneficial role of mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEVs) in cutaneous wound healing has been widely reported, but the field of photoaging remains to be explored. Our results suggested that human umbilical cord MSC-derived sEVs (hucMSC-sEVs) intervention could effectively alleviate skin photoaging phenotypes in vivo and in vitro, including ameliorating UV-induced histopathological changes in the skin and inhibiting oxidative stress and collagen degradation in dermal fibroblasts (DFs). Mechanistically, pretreatment with hucMSC-sEVs reversed UVA-induced down-regulation of pregnancy zone protein (PZP) in DFs, and achieved photoprotection by inhibiting matrix metalloproteinase-1 (MMP-1) expression and reducing DNA damage. Clinically, a significant decrease in PZP in AK and SCC in situ samples was observed, while a rebound appeared in the invasive SCC samples. Collectively, our findings reveal the effective role of hucMSC-sEVs in regulating PZP to combat photoaging and provide new pre-clinical evidence for the potential development of hucMSC-sEVs as an effective skin photoprotective agent.© The Author(s) 2024. Published by Oxford University Press.