“Imposters” lurking in the extracellular matrix-mimicking hydrogel trap inflammatory mediators for the treatment of inflammatory wounds

In this study, a synergistic treatment strategy is proposed, which combines an extracellular matrix (ECM)-mimicking hydrogel with nanodecoys (M1-NDs) for the treatment of inflammatory wounds. This method achieves targeted intervention in the inflammatory microenvironment by embedding M1 macrophage membrane-derived nanodecoys into the ECM-mimicking hydrogel matrix (M1-CHA). M1-NDs specifically bind to free lipopolysaccharides (LPS) and pro-inflammatory cytokines at the wound site, thereby blocking the interaction between LPS and Toll-like receptor 4 (TLR4) on host cells and inhibiting the activation of the NF-κB signaling pathway. Meanwhile, M1-NDs are combined with a hydrogel prepared mainly from collagen, hyaluronic acid, and sodium alginate. This hydrogel not only serves as a protective carrier for M1-NDs but also mimics the natural extracellular matrix (ECM) to promote collagen regeneration, inhibit matrix metalloproteinases (MMPs), and remodel the ECM. Animal experiments have shown that M1-CHA effectively suppresses inflammation, promotes collagen precipitation, remodels the ECM, and ultimately facilitates the healing of inflammatory wounds. In summary, the M1-CHA holds great potential for the treatment of inflammation wounds. • M1 macrophage membrane-based nanodecoys (M1-NDs) specifically capture LPS and inflammatory cytokines, blocking their interaction with host cells and effectively suppressing excessive inflammatory responses. • M1-NDs attenuate hyperactivation of the TLR4/NF-κB signaling pathway, thereby mitigating inflammation exacerbation. • The biomimetic hydrogel composed of collagen, hyaluronic acid, and sodium alginate (CHA) mimics extracellular matrix functions, inhibits MMP activity, promotes tissue regeneration and serves as a sustained-release carrier for nanodecoys. • The M1-ND loaded CHA (M1-CHA) synergistically modulates the inflammatory microenvironment and promotes angiogenesis, tissue repair, and extracellular matrix (ECM) remodeling. • M1-CHA represents a novel therapeutic strategy for the treatment of inflammatory wounds. 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.