Palmitoyl Pentapeptide-4-Functionalized Ethosomes with Surfactant-Tailored Bilayers for Enhanced Dermal Delivery of Chlorogenic Acid

Background/Objectives: Chlorogenic acid (CGA), a potent antioxidant polyphenol, scavenges reactive oxygen species (ROS) and ameliorates oxidative stress-induced dermal extracellular matrix deterioration. However, its high hydrophilicity causes poor stratum corneum partitioning, insufficient dermal retention and low bioavailability. This study aimed to develop a surfactant-optimized, palmitoyl pentapeptide-4 (PP-4)-functionalized ethosomal system to enhance dermal retention and skin-protective efficacy of CGA. Methods: Binary nonionic surfactants were employed to optimize ethosome performance, followed by noncovalent PP-4 bilayer functionalization. Vesicle physicochemical properties and molecular interactions were characterized. Ex vivo skin permeation, cellular uptake, cytoprotection, intracellular ROS scavenging, and extracellular matrix-related gene expression were evaluated. Results: Surfactant-optimized ethosomes (CGA-ES, ~146 nm, −2.0 mV) exhibited higher encapsulation efficiency (92 ± 2%) and superior transdermal permeation versus surfactant-free vesicles. Subsequent PP-4 insertion reduced particle size to ~137 nm, reversed charge to +6.7 mV, and retained favorable encapsulation (83 ± 2%), forming mixed unilamellar–multilamellar structures. FTIR revealed the formation of hydrogen-bonded networks at phospholipid interfaces, underpinning superior colloidal uniformity and stability. The modified vesicles achieved enhanced total skin deposition and 1.2-fold higher dermis targeting efficiency compared with CGA-ES, along with improved cellular internalization, superior cytoprotection, and 2.4-fold stronger ROS scavenging under oxidative stress. The system effectively suppressed oxidative stress-induced upregulation of matrix metalloproteinase-1 and -3 (MMP-1/MMP-3) and restored type I collagen expression. Blank PP-4-modified ethosomes verified intrinsic peptide bioactivity, demonstrating complementary protection between CGA and PP-4. Conclusions: Binary-surfactant optimization enhances ethosomal colloidal performance and skin permeation. PP-4-mediated bilayer remodeling further promotes intradermal deposition. This dual-functional nanoplatform achieves combined skin-protective effects of CGA and surface-bound PP-4, providing a formulation basis for further in vivo evaluation and a potential strategy for topical delivery of hydrophilic polyphenols.