A Repurposed Olmesartan-Loaded Hyaluronic Acid-Functionalized Lecithin–Chitosan Nanoparticle Hydrogel for Enhanced Topical Delivery in Diabetic Wound Healing

A novel topical nanocarrier-based hydrogel system incorporating olmesartan medoxomil (OLM) was designed to enhance diabetic wound healing through targeted skin delivery. OLM was efficiently encapsulated within lecithin–chitosan hybrid nanoparticles (LCNPs), which were subsequently functionalized with hyaluronic acid (HA) to improve dermal adhesion, biocompatibility, and sustained release. The optimized OLM-HA-LCNPs exhibited a nanoscale size of 324.28 ± 5.71 nm, a negative zeta potential (-39.64 ± 3.2 mV), and a high entrapment efficiency of 89.86 ± 3.15%. In vitro release studies demonstrated a controlled, biphasic OLM release pattern over 24 h following Weibull kinetics, confirming diffusion erosion-controlled release behavior. Incorporation into a hydrogel base preserved pseudoplastic rheology, optimal pH (6.3 ± 0.2), and superior spreadability (35.26 cm2). In streptozotocin-induced diabetic rats, the OLM-HA-LCNP hydrogel produced 93.5% wound closure after 14 days, compared with 87.6%, 77.1%, and 90.8% for the marketed reference, plain HA–LCNPs, and OLM-pure treatments, respectively. OLM-HA-LCNP hydrogel also increased CAT, SOD, and GSH levels by 2.7, 1.45, and 2.16 fold, respectively, and reduced MDA levels by 77% compared with diabetic controls. Histological and immunohistochemical findings further demonstrated improved epidermal regeneration, collagen deposition, and normalization of VEGF and MMP-9 expression. Collectively, these findings demonstrate that HA-functionalized lecithin–chitosan nanoparticles incorporated into a hydrogel provide an effective platform for sustained topical OLM delivery and enhanced therapeutic performance in diabetic wound healing.