Multifunctional hybrid lipid-polymeric nanoparticle enabling resveratrol and siRNA co-delivery for enhanced cutaneous wound repair.

Chronic ulcers impose a significant global healthcare burden due to the limited availability of effective and durable treatments. Impaired spatial and temporal coordination of immune, epithelial, and endothelial responses contributes to persistent inflammation and defective tissue repair. To address this complexity, in this study, we report the rational design and characterization of a hybrid lipid-polymeric nanoparticle (HLPN) platform for prolonged topical co-delivery of resveratrol (RSV), targeting oxidative and inflammatory pathways, and siRNA against matrix metalloproteinase-9 (siMMP9), a key mediator of chronicity. The optimized HLPNs exhibited a mean diameter of ∼180 nm, low polydispersity (PDI <0.2), and positive surface charge (∼20 mV), with high RSV encapsulation efficiency (98%). Surface-complexed siRNA remained protected from RNase degradation for up to 24 h. Incorporation of HLPNs into a hydroxyethylcellulose hydrogel resulted in favorable colloidal properties, leading to enhanced penetration and retention of the therapeutic agents in both intact and barrier-impaired skin. HLPN effectively mediated the cellular uptake of siRNA, resulting in significant MMP-9 gene silencing (≈11-36.5-fold reduction). The co-delivery system also markedly decreased intracellular reactive oxygen species and pro-inflammatory cytokines TNF-α and IL-6 (≈3.8 and 12.9-fold). Importantly, lipopolysaccharide-induced impairment of fibroblast migration was reversed, with the HLPN-RSV-siMMP9 formulation increasing cell migration compared with untreated inflamed controls. Together, these findings demonstrate that the multifunctional HLPN platform developed enables effective multimodal modulation of inflammatory and proteolytic pathways, representing a promising nanotherapeutic strategy for chronic wound management.