Transdermal Delivery of Hyaluronate-Conjugated Formyl Peptide Receptor 2 Agonistic Peptide Ameliorates Bleomycin-Induced Skin Fibrosis

Systemic sclerosis is a severe autoimmune disorder defined by progressive tissue hardening and inflammatory infiltration that affects the skin and major internal organs. The formyl peptide receptor 2 (FPR2) agonist, WKYMVm (Wm), shows promise for alleviating dermal fibrosis; however, its clinical translation is impeded by the need for invasive subcutaneous injection to bypass the skin barrier. To overcome this limitation, we developed a noninvasive topical delivery system by conjugating Wm to hyaluronic acid (HA), a biopolymer known for its transdermal delivery properties. In a bleomycin (BLM)-induced murine model of fibrosis, we assessed the therapeutic efficacy of the HA-Wm conjugate and its capacity to penetrate the skin barrier. Topical application of the HA-Wm conjugate exhibited enhanced skin permeation relative to free Wm, resulting in marked reductions in both dermal layer thickness and collagen accumulation within the fibrotic lesions. Mechanistically, HA-Wm treatment markedly decreased the numbers of α-smooth muscle actin-positive myofibroblasts and CD68-positive macrophages in the fibrotic skin. The HA-Wm treatment inhibited macrophage migration in vitro and reduced the serum concentrations of interferon-γ and tumor necrosis factor-α in BLM-treated mice. Importantly, the therapeutic effects of HA-Wm were abolished in <i>Fpr2</i>-deficient mice, confirming an FPR2-dependent mechanism of action. Collectively, these results demonstrate that topical treatment of HA-Wm alleviates skin fibrosis and inflammation via an FPR2-dependent pathway, representing a promising noninvasive therapeutic avenue for fibrotic skin disorders such as systemic sclerosis.