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ORIGINAL RESEARCH article
Front. Med.
Sec. Dermatology
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1529936
This article is part of the Research TopicGenetics (SKINOMICS): New Trends in Skin Aging Research and Clinical ApplicationView all articles
Protecting and rejuvenating skin aging by regulating endogenous hyaluronan metabolism using adipose-derived stem cell-secreted siRNAs
Provisionally accepted
Benben Sun1Yanqiu He1Lingzhu Zhang1
Siyu Liu2Menghan Chen1Jinmeng Pan1Jingwen Fang1Ye Wang1Haiyue Jiang2Xia Liu2Chen-Yu Zhang1,2
Jing Li1*- 1Nanjing University, Nanjing, China
- 2Peking Union Medical College Hospital (CAMS), Beijing, Beijing Municipality, China
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Background: Loss of moisture is the primary cause of skin aging and dysfunction. The skin’s hydration largely depends on hyaluronan (HA) and its ability to retain water. Ultraviolet (UV) irradiation, which accounts for 80% of skin aging (commonly referred to as photoaging), gradually disrupts the balance of HA metabolism, leading to a reduction in HA levels, dehydration and, ultimately, the formation of wrinkles. Methods: In this study, we develop an RNAi-based strategy to treat aged skin by modulating endogenous HA metabolism. Hyaluronidase 2 (HYAL2), an enzyme responsible for HA degradation, is selected as the therapeutic target, given its significant upregulation in photoaged skin. To deliver the siRNA targeting HYAL2 to the skin, human adipose-derived stem cells (ADSCs) are engineered to stably express and secrete HYAL2-targeting siRNAs (ADSC/siRH) via small extracellular vesicles (sEVs). Results: In vitro experiments demonstrate that ADSC-delivered siRNAs are successfully internalised by recipient cells, where they restore UV-induced HA reduction by inhibiting HYAL2 expression. In vivo experiments reveal that subcutaneous implantation of engineered ADSCs prior to UV exposure significantly protects mouse skin from accelerated HA degradation, helping to retain water content and prevent UV-induced dryness. Furthermore, application of engineered ADSCs to aged mouse skin can markedly restore HA and water content, effectively smoothing deep wrinkles and improving skin appearance. Conclusion: We develop an effective biological strategy to combat skin aging and damage by preserving endogenous HA levels, which could be applied for facial rejuvenation in the future.
Keywords: Skin Aging, Hyaluronan (HA), Extracellular vesicles (EVs), Adipose-Derived Stem Cells (ADSCs), siRNA therapy
Received: 18 Nov 2024; Accepted: 11 Apr 2025.
Copyright: © 2025 Sun, He, Zhang, Liu, Chen, Pan, Fang, Wang, Jiang, Liu, Zhang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jing Li, Nanjing University, Nanjing, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.