Abstract

Inflammatory wounds are characterized by persistent inflammation and impaired healing functions, with pathogenesis linked to dysregulated molecular signaling pathways and excessive release of pro-inflammatory cytokines. Lipopolysaccharide (LPS), a common pathogen-associated molecular pattern, triggers inflammatory responses by activating Toll-like receptor 4 (TLR4) and its downstream NF-κB signaling pathway. This exacerbates inflammation and delays wound healing. To address this issue, we developed an extracellular matrix (ECM)-mimicking hydrogel loaded with nanodecoys to achieve synergistic anti-inflammatory and tissue-regenerative effects. The nanodecoys (M1-NDs) were fabricated from the membranes of M1-type macrophages stimulated with LPS and IFN-γ. In inflammatory environments, M1-NDs act as “imposters” for M1 macrophages, retaining highly expressed TLR4 and specific receptors associated with inflammatory cytokines. They selectively capture LPS and pro-inflammatory cytokines, thereby inhibiting NF-κB activation and attenuating the inflammatory cascade. An ECM-mimicking hydrogel composed of collagen, hyaluronic acid, and sodium alginate (CHA) serves as a carrier for M1-NDs (M1-CHA), preserving bioactivity and enabling localized release. Experimental results confirmed that M1-CHA accelerates healing of inflammatory wounds by neutralizing LPS and pro-inflammatory cytokines, blocking downstream TLR4 signaling, suppressing inflammation, alleviating oxidative stress, and simultaneously promoting collagen deposition, ECM remodeling and vascularization. This dual-functional strategy provides a novel therapeutic approach for inflammatory wounds.