Caffeoyl hexapeptide-9 (CH-9) is a novel cosmetic peptide designed by conjugating hexapeptide-9 (H-9), a known collagen-mimetic peptide with established skin anti-aging activity, with caffeic acid (CA) via an amide bond, leveraging peptide-drug conjugate (PDC) design principles. In ultraviolet (UV)-irradiated cellular and skin models, CH-9 outperformed H-9 in preserving cell viability, restoring collagen types I, III, and IV, and suppressing interleukin-6 and -8 secretion. Additionally, its direct antioxidant activity, absent in H-9, was demonstrated in vitro by scavenging of hydroxyl and peroxyl radicals. Molecular docking indicated CH-9 interacted with the catalytic domain of matrix metalloproteinase 2 (MMP2), a key enzyme in collagen degradation during photoaging, suggesting a potential inhibition of its activity. Molecular dynamics (MD) simulations revealed an improved insertion of CH-9 into a stratum corneum (SC) lipid bilayer compared to H-9, consistent with enhanced skin permeation in vivo. Moreover, CH-9 exhibited improved aqueous and cosmetic serum stability over CA. In a 28-day clinical study, topical application of CH-9 significantly improved skin elasticity and firmness compared to H-9. This work demonstrates that the PDC-based conjugate CH-9 combines enhanced anti-photoaging efficacy with improved transdermal permeation and stability, highlighting a promising strategy for the development of advanced cosmetic ingredients.

Objective: To evaluate Oligopeptide‐215, a biomimetic peptide engineered from amphibian skin secretions, for its dual capacity to restore skin barrier homeostasis by concurrently targeting physical barrier proteins and inflammatory pathways via JAK–STAT and NF‐κB modulation. Methods: In vitro models used UVB‐damaged HaCaT keratinocytes, LPS‐stimulated RAW264.7 macrophages, and IL‐4/IL‐13‐stimulated HaCaT cells. Assays included cell viability (MTT), migration (scratch), adhesion, barrier proteins (FLG/LOR; ELISA/IF), signaling phosphoproteins (pJAK1/pTYK2/pSTAT3/pSTAT6/pNF‐κB; IF), and inflammatory mediators (NO/PGE₂/TNF‐α/IL‐6/IL‐1β; ELISA). Results: Oligopeptide‐215 antagonizes IL‐13/IL‐4‐mediated JAK–STAT6/STAT3 signaling, thereby restoring expression of critical barrier proteins FLG and LOR. Additionally, it suppresses inflammatory responses by inhibiting NF‐κB‐dependent cytokine production. In UVB‐damaged keratinocytes, Oligopeptide‐215 promotes cellular repair through enhanced proliferation, adhesion, and migration. Conclusion: These findings revealed an innovative repairing mechanism combining physical barrier with immunologic barrier, and established Oligopeptide‐215 as a potential skincare ingredient for skin barrier dysfunction.