Abstract
Hydrophobic phytochemicals have emerged as potent active agents in dermatological and cosmeceutical applications due to their exceptional antioxidant, photoprotective, and anti-inflammatory attributes; however, their translation into effective topical formulations remains severely compromised by poor aqueous solubility, rapid photodegradation, and deficient stratum corneum permeation. In this study, we report the biomimetic design and synthesis of self-assembled peptide-polymer hybrid nanostructures engineered specifically for the stable encapsulation and sustained topical release of hydrophobic polyphenols, using trans-resveratrol as a model phytochemical. The hybrid conjugates were synthesized by coupling a self-assembling diphenylalanine-based peptide motif (Ac-Phe-Phe-Cys-NH2) with maleimide-functionalized methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-b-PCL-Mal) via bio-orthogonal thiol-maleimide addition. Driven by cooperative hydrogen bonding, π–π aromatic stacking, and hydrophobic collapse, the resulting amphiphilic hybrids spontaneously assembled in aqueous media into uniform, core-shell nanospheres exhibiting an average hydrodynamic diameter of 92.4 ± 3.8 nm and a narrow polydispersity index. Spectroscopic investigations verified that the embedded peptide domains adopted an antiparallel β-sheet architecture, substantially enhancing the mechanical integrity and thermal stability of the macromolecular assembly. The nanostructures demonstrated high encapsulation efficiency (88.6 ± 2.1%) and effectively shielded the entrapped phytochemical against ambient and ultraviolet photolysis. In vitro release assays revealed a biphasic, sustained diffusion profile governed by non-Fickian kinetics under physiological skin conditions (pH 5.5). Furthermore, ex vivo skin permeation studies utilizing Franz diffusion cells demonstrated enhanced follicular and trans-epidermal deposition within the viable epidermis and dermis, accompanied by negligible transdermal systemic bypass. Cellular assays in human dermal fibroblasts confirmed superior cytoprotection against oxidative insult, establishing these biomimetic hybrid nanostructures as an advanced platform for topical cosmetic formulations.
