Introduction

Many peptides have been shown to promote collagen production, reduce matrix metallo proteinase (MMP) activity, improve skin elasticity, and minimize wrinkles. Hexapeptide 9 (Figure 1) is one of the most important example. As a collagen peptide, hexapeptide 9 (Gly-Pro-Gln-Gly-Pro-Gln)has been designed to provide curative and/or preventive treatment for skin aging and to enhance skin appearance.[1] Hexapeptide 9 is a signal peptide with the same amino acid sequence as human collagen and has been demonstrated to combat the aging process by promoting collagen production, cell migration, and differentiation. Under normal conditions, the body can efficiently metabolize and remove GABA, LA, and hexapeptide 9 without side effects.[2]

Transdermal delivery of hexapeptide 9

Of all the human organs, the skin is the first to display visible signs of aging and hence vital in maintaining beauty and confidence. Over time,the skin loses its elasticity, and wrinkles appear owing to the reduced levels of collagen and elastin fibers. Because of the aging global population, the demand for anti-aging products has increased. Compared with traditional anti-aging ingredients, peptides are highly regarded fortheir excellent specificity and biosafety profiles. Many peptides have been shown to promote collagen production, reduce matrix metalloproteinase (MMP) activity, improve skin elasticity, and minimize wrinkles. Examples include copper tripeptide-1, hexapeptide-9 (HP9),palmitoyl tripeptide-1, palmitoyl tripeptide-5, palmitoylpentapeptide-4, and palmitoyl hexapeptide-12. In addition to the natural wrinkles caused by aging (static lines), expression wrinkles formowing to the contraction of facial muscles (dynamic lines). [2]

Facial wrinkles include static and dynamic lines formed through different mechanisms and require diverse treatment approaches. Peptides perform well in anti-aging and wrinkle removal but exhibit poor transdermal efficiency. In this work, a novel neuro-soothing ionic liquid, GALA, prepared from γ-aminobutyric acid (GABA) and lactic acid (LA), is applied in the transdermal delivery of hexapeptide 9, which promotes collagen production. This treatment aims to remove dynamic and static lines simultaneously, and the human endogenous feature of GABA, LA, and hexapeptide 9 guarantees high biosafety of the system. The in-vitro transdermal, cellular, animal, and clinical experiments indicate that GALA is a safe and effective enhancer. GALA enhances the local penetration of hexapeptide 9 by altering the skin barrier structure, resulting in cumulative permeation and subcutaneous retention, respectively, 4.79 and 7.89 folds of that without enhancers after 12 h. GALA also enables hexapeptide-9 to combat root aging, mainly by activating the PPAR signaling pathway, leading to lower degrees of ultraviolet-induced oxidative stress, inflammation, epidermal hyperplasia, and the degradation of collagen and elastic fibers. Therefore, the combination of GALA and hexapeptide 9 has excellent potential in anti-wrinkle and antiaging treatments. This work's experimental and theoretical studies will further advance the clinical use of bioactive ionic liquids as transdermal enhancers.[2]

Novel Cyclized Hexapeptide-9 Outperforms Retinol Against Skin Aging

The functionality and regenerative capacity of skin progressively deteriorate with aging. Topical use of peptides with a hyper-safety profile has been implicated in replacing retinol for skin anti-aging use, but is limited due to low stability and poor skin permeability.In this randomized, double-blinded, active- and vehicle-controlled clinical trial, we aim to evaluate the efficacy of an innovative cyclized hexapeptide 9 with increased stability and skin permeability on skin aging compared to retinol. Methods: Healthy volunteers with aging skin were randomly assigned to twice-daily topical use of 0.002% cyclized hexapeptide 9 serum, 0.002% retinol serum, or vehicle serum for 56 days. Cyclized hexapeptide 9 treatment significantly decreased the number, area, and roughness of both crow's feet (-2.20, 95% CI: -4.38, -0.03; -3.95, 95% CI: -5.80, -2.11; -1.95, 95% CI: -3.30, -0.59, respectively) and forehead wrinkles (-2.88, 95% CI: -4.21, -1.56; -4.90, 95% CI: -5.97, -3.82; -3.96, 95% CI: -5.92, -2.01, respectively), while retinol only decreased the area of crow's feet (-2.23, 95% CI: -3.86, -0.60) and the number and area of forehead wrinkles (-1.05, 95% CI:-1.69, -0.41). Except for the roughness of crow's feet, cyclized hexapeptide 9 demonstrated significantly larger extent of effects than retinol did on all other outcomes. Furthermore, long-term use of cyclized hexapeptide 9 showed time-dependent augmentation in its potency to reduce the number of crow's feet, and the number, area, and roughness of forehead wrinkles. Conclusions: In conclusion, cyclized hexapeptide 9 is more potent than retinol in improving skin aging-related symptoms, especially for long-term use. Cyclization of collagen peptides may present a preventive/therapeutic option for skin aging.[1]

References

[1] Chang H, Tao K, Yang Y, et al. Novel Cyclized Hexapeptide-9 Outperforms Retinol Against Skin Aging: A Randomized, Double-Blinded, Active- and Vehicle-Controlled Clinical Trial. J Cosmet Dermatol. 2025;24(7):e70290. doi:10.1111/jocd.70290

[2] Wang M, Wang Z, Liu T, et al. Pioneering ionic liquids in neuro-soothing: Enhanced transdermal delivery of collagen peptides and their synergistic anti-aging functions. Mater Today Bio. 2025;31:101527. Published 2025 Jan 27. doi:10.1016/j.mtbio.2025.101527