Gynostemma pentaphyllum-derived extracellular vesicles alleviate skin aging by destabilizing STING

Skin aging represents a multifaceted degenerative process that predisposes to dermatological pathologies, including infections, dermatitis, and malignancies, causing great physical and psychological distress to patients. Conventional therapies, including topical antioxidants and sunscreens, have shown limited efficacy with safety concerns that continue to pose a substantial challenge in the treatment of skin aging. In this context, we pioneered the therapeutic application of Gynostemma pentaphyllum -derived extracellular vesicles (GPEVs), demonstrating their unprecedented efficacy in alleviating UVB-induced skin aging. Specifically, GPEVs restored epidermal integrity by inhibiting collagen degradation and DNA damage, while improving skin hydration. In vitro, the administration of GPEVs led to reduced SA-β-gal activity, enhanced cell proliferation, and diminished senescence-associated secretory phenotype (SASP). Mechanistically, GPEVs prevented CTCF-mediated transcriptional activation of aging-related genes via promoting targeted STING degradation. Notably, the therapeutic effects of GPEVs were entirely abolished upon STING agonism, thereby confirming the target specificity. Our study not only establishes GPEVs as a biocompatible nanotherapeutic agent for addressing skin aging but also represents a paradigm-shifting strategy for the utilization of plant-derived extracellular vesicles, bridging critical gaps in current anti-aging dermatology. UVB radiation triggers the up-regulation of STING, activating the TBK1-CTCF pathway and causing photoaging. Extracellular vesicles derived from Gynostemma pentaphyllum (GPEVs) effectively promote STING degradation, reducing CTCF-mediated aging-related gene transcription, protecting against UVB-induced skin aging. • This study presents the inaugural successful isolation and characterization of GPEVs. • GPEVs exhibit high efficacy against UVB-induced skin aging both in vivo and in vitro. • GPEVs block CTCF-mediated SASPs transcription by promoting STING degradation.