Topical application of Tea leaf-derived nanovesicles reduce melanogenesis by modulating the miR-828b/MYB4 axis: better permeability and therapeutic efficacy than conventional tea extracts

Over-pigmentation of skin caused by excessive melanin production faces the challenges of limited therapeutic effects and safety, the conventional tea leaf extract (TET) for pigmentation treatment has the disadvantages of residual harmful substances, low penetration efficiency, here we propose the tea leaf-derived nanovesicles (TLNVs) as natural nanomaterials that combine bioactive components in tea leaves and exosome-like delivery advantages for targeting over-pigmentation treatment. This study extracted TLNVs from fresh tea leaves by ultracentrifugation and characterized them by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and secondary metabolites composition analysis. In vitro, TLNVs exhibited stronger radical scavenging ability and tyrosinase inhibitory effect than conventional tea leaf extract, while inhibiting B16-F10 cell proliferation and melanin synthesis. Based on these in vitro results, we further evaluated the anti-pigmentation effects of TLNVs in an uvB-induced pigmented mouse model, in which TLNVs markedly reduced epidermal melanin deposition and epidermal thickness while increasing dermal thickness and collagen volume fraction. TLNVs effectively suppressed the expression of inflammatory cytokines (TNF-α and IL-1β) and promoted melanoautophagy by upregulating LC3B and downregulating P62. Moreover, confocal laser scanning microscopy (CLSM) analysis of fluorescently labeled TLNVs confirmed their penetration ability into the deep dermis, reaching approximately 200 μm. Mechanistic studies demonstrated that miR-828b in TLNVs directly targeted MYB 4 via PI3K/AKT pathway and downregulated melanogenesis regulators such as MITF and TYR. to reduce melanin production. Overexpression of MYB 4 reversed the inhibitory effects of miR-828b on melanogenesis, confirming the specificity of this regulatory axis. This study is the first to confirm that TLNVs, as natural nanomaterials, exert multifunctional properties in combating skin pigmentation through the miR-828b/ MYB 4 axis. These include antioxidation, anti-inflammation, and the promotion of autophagy activity. TLNVs with high transdermal permeability and low toxicity provide a safer strategy for coping with pigmented skin diseases and sustainable tea leaf resource utilization. • Topically applied Tea leaf-derived nanovesicles (TLNVs) effectively inhibit pigmentation and outperform conventional tea extracts. • TLNVs deliver miR-828b to target MYB 4 and downregulate melanin synthesis. • TLNVs are rich in miRNA, polyphenols and flavonoids, and exhibit superior antioxidant, anti-inflammatory and pro-autophagy effects. • TLNVs achieve deep dermal penetration (about 200 μm) with high transdermal efficiency. • The efficacy of TLNVs in inhibiting pigmentation was confirmed using both classic melanogenesis cell models and pigmented mice models.