Chitosan quaternary ammonium/sodium alginate double-network hydrogel loaded with interleukin-11-targeting siRNA-lipid nanoparticles for scarless wound healing

Dual-Crosslinking Strategy: A dual network combining genipin-mediated Schiff base dynamic bonding and Ca 2+ coordination cross-linking for mechanical reinforcement and nanoparticle anchoring. • Nucleic acid drug delivery and gene intervention: IL-11 siRNA-loaded LNPs anchored in hydrogel enable sustained release, silencing IL-11 and fibrotic genes to inhibit myofibroblast activity and remodel collagen for anti-fibrosis. • Scar-free healing promotion: SQG/si IL11 @NPs dressing reduces scar index and thickness, restores collagen I/III ratio, downregulates α-SMA and TGF-β1, enabling near scar-free skin regeneration. Hypertrophic scars often cause functional impairment and aesthetic damage, thereby affecting patients' daily life and comfort. Moreover, existing therapies have limited efficacy and are prone to recurrence. To achieve precise genetic intervention, this study constructed a time-controlled release polysaccharide hydrogel dressing for the targeted delivery of IL-11 siRNA. This dressing is based on a chitosan quaternary ammonium (QCS)/sodium alginate (SA) double-network structure hydrogel (SQG) and loaded with cationic lipid nanoparticles (si IL11 @NPs), forming an “integrated drug-loading and cross-linking” system. SQG hydrogel also shows good antibacterial activity and anti-inflammatory properties, which is helpful to establish a wound microenvironment that inhibits scar hyperplasia. It continuously releases siRNA during the mid-to-late stage of wound healing (days 5–9). Cell experiments showed that the released nanoparticles were efficiently internalized by TGF-β1-induced myofibroblasts, significantly inhibiting their migration and proliferation and downregulating the expression of IL-11 and the typical fibrotic genes COL1A1, FN1, and ACTA2. In the rabbit ear scar model, this dressing promoted wound healing, inhibited late-stage hypertrophy, reduced the scar elevation index and thickness, improved collagen alignment and the type I/III collagen ratio, and downregulated the expression of α-SMA and TGF-β1. In summary, the SQG/si IL11 @NPs hydrogel dressing shows good potential and provides a new option for inhibiting hypertrophic scar formation in wound treatment.