The integration of nanotechnology into regenerative medicine has the potential to revolutionize diagnosis and treatment outcomes. Nanotechnology enables the design and manufacture of biomaterials with excellent properties and controllable topography that mimic the extracellular matrix (ECM). Mimicking the extracellular matrix structure is a promising approach in skin regenerative medicine. Electrospun nanofibers have a similar architecture to ECM and provide sites for cell attachment, proliferation, and maturation. In addition, the high surface-to- volume ratio of nanofibers and their high loading capacity make them ideal for designing drug delivery systems. Biomolecule delivery at a programmed rate leads to the release of drugs at the target site in the regenerative medicine field. In this study, arginine and berberine were encapsulated in the hyaluronic acid core nanofiber, and gelatin polymer was used as the shell layer. Uniform and bead-free core−shell nanofibers with ∼175 nm diameter were produced. The interaction between cationic arginine−berberine and anionic hyaluronic acid, as well as the protective role of the shell layer, leads to the sustained release of loaded biomolecules. In vitro studies of L929 fibroblast cells on nanofibers confirmed the cytocompatibility and proliferative properties of core−shell nanofiber mats. In vivo wound healing studies on BALB/c mice demonstrated that wound healing is faster when arginine and berberine are incorporated into the core−shell nanofiber mats. Real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) data show that treatment with arginine−berberine-loaded nanofibers accelerates skin regeneration by regulating the expression of IL-6, TNF-α, TGF-β, and VEGF. Overall, the fabricated core−shell nanofiber provides a noninvasive platform for entrapment and controlled release of active biomolecules to improve therapeutic outcomes.

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