Peptides are molecules composed of two or more amino acids linked by peptide bonds, and they play essential biological roles. In recent decades, peptides have become pivotal bioactive ingredients in pharmaceuticals and cosmetics due to their unique features. Originally developed for therapeutic purposes, peptides have gained popularity in the cosmetic field, providing solutions for anti-aging, whitening, moisturizing, and skin repair. Moreover, innovations such as artificial intelligence-assisted peptide design, efficient delivery systems, and the integration of multifunctional ingredients have significantly contributed to the industry’s rapid evolution. This review explores the historical milestones of peptides in medicine and cosmetics, delves into cutting-edge synthesis technologies, and dissects the molecular mechanisms behind their cosmetic properties. Research in medicinal peptides has promoted the development of cosmetic peptides. Despite their potential, challenges such as stability, bioavailability, and cost-effective production remain barriers to widespread adoption. Future studies should focus on enhancing peptide stability, developing synergistic formulations, and conducting large-scale clinical trials to validate long-term efficacy. With continuous innovation, peptides are poised to redefine the cosmetic industry, bridging the gap between pharmaceuticals and skincare for safer and more effective solutions.

This review systematically summarizes research progress in the evaluation of the effectiveness and safety of the transdermal absorption of cosmetics, focusing on the classification, applicability, and relevant regulations of different evaluation methods. Transdermal absorption refers to the process in which active ingredients enter the epidermis, dermis, and other parts of the skin through the skin barrier and exert their effects. The article first classifies the in vitro and in vivo evaluation methods of transdermal absorption. It also provides a detailed overview of the regulations and standards for in vitro transdermal absorption, compares the standards of different institutions, and highlights the diffusion cell method, developed by scientists at Procter & Gamble, which is the mainstream method for in vitro testing. In addition, the paper summarizes the utilization of modern testing techniques such as high-throughput screening technology, mass spectrometry imaging, Raman spectroscopy, and confocal microscopy in the study of transdermal absorption and introduces the working principles of various instruments and their specific application cases in transdermal absorption studies.

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.

Efficient delivery of bioactive hydrophilic peptides across the stratum corneum (SC) is a major challenge due to the restricted permeation by the highly ordered lipid matrix, particularly for large or polar molecules. Oligopeptide-215 (OP215) is a biomimetic peptide with reported benefits in promoting cellular repair through enhanced proliferation, adhesion, and migration, but its size and polar/charged residues may limit transport through the SC. Here, we used atomistic molecular dynamics (MD) simulations to investigate whether caffeoyl hexapeptide-9 (CH-9), an anti-aging peptide-caffeic acid conjugate with enhanced skin permeation, can improve OP215 diffusivity across an SC lipid bilayer model. Both OP215 and CH-9 adsorbed onto the bilayer surface and partially inserted below the lipid headgroup region, with OP215 insertion mediated primarily by methionine sidechains and CH-9 insertion by the caffeoyl group. In the co-peptide system, CH-9 co-clustered with OP215 and modestly disrupted free fatty acid packing within the SC lipid bilayer. Position-dependent diffusivity calculations further showed that CH-9 increased the effective diffusivity of OP215 across the bilayer interior by approximately 13%, primarily by enhancing local diffusivity just below the bilayer surface. These results suggest that on top of being an effective anti-aging peptide, CH-9 may act as a permeation-enhancing co-peptide by inducing lipid packing disorder, thereby facilitating OP215 diffusion through the SC lipid matrix. This research provides molecular-level insight into the design of multi-peptide systems for improved topical delivery of functional skincare peptides.