Research on the interactions between multifunctional nanocomposite hydrogels and biological interfaces is a hot topic in the field of biomedical materials. Its primary objective is to employ low-dimensional nanofillers with intrinsic bioactivity to achieve multiple functions of hydrogel dressings, including targeted antibacterial activity, antioxidation, immunomodulation and mechanical adaptability in the microenvironment of infected chronic wounds, by tuning their non-covalent/dynamic covalent interactions with polymer networks.

Poly(phenol-imidazole) nanosheets are used to endow hydrogels with mechanical reinforcement and photothermal responsiveness. This composite hydrogel constructs a thermoresponsive natural polysaccharide-polypeptide network using gelatin (10 wt%) and κ-carrageenan (1.8 wt%), with lignin-derived poly(phenol-imidazole) nanosheets (PIM-NS) incorporated. Rich in phenolic hydroxyl and imidazole groups on the surface, PIM-NS forms multivalent interfacial bonds with the matrix through hydrogen bonding, π-π stacking and ionic bonds. Such interfacial interactions not only markedly improve the mechanical strength of the hydrogel (tensile strength increased to 33 kPa, compressive strength reaching 166 kPa, and Young’s modulus around 50 kPa, close to that of native skin), but also grant the hydrogel remotely controllable mechanical adaptability. Under 808 nm near-infrared (NIR) irradiation, PIM-NS achieves a high photothermal conversion efficiency of 55.79%, rapidly raising the surface temperature of the hydrogel to 47 °C and triggering gel-sol transition. This enables in-situ adaptation to irregular wound contours and firm tissue adhesion after cooling.
Poly(phenol-imidazole) nanosheets are utilized to realize physical antibacterial and antioxidant therapy for infected wounds. The microenvironment of infected diabetic wounds is frequently accompanied by severe bacterial infection and oxidative stress. The imidazolium quaternary ammonium groups in PIM-NS can physically disrupt bacterial membrane integrity. Combined with the photothermal effect, the composite hydrogel exhibits broad-spectrum antibacterial activity against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) under 808 nm NIR irradiation, with an antibacterial rate exceeding 99%. In addition, its phenolic hydroxyl structure confers the hydrogel strong DPPH and ABTS radical scavenging capacity, which effectively regulates the level of reactive oxygen species (ROS) at wound sites and alleviates inflammatory responses.

Transcriptomics and animal models are applied to evaluate its wound-healing-promoting and immunomodulatory mechanisms. In a streptozotocin-induced diabetic mouse model of infected full-thickness skin defect, the PIM-NS hydrogel-1 + NIR treatment group showed significantly accelerated wound closure. Histological staining (H&E, Masson) demonstrated enhanced re-epithelialization, increased collagen deposition and angiogenesis. Transcriptome sequencing analysis revealed that 101 differentially expressed genes (DEGs) in the treatment group were significantly enriched in pathways related to inflammatory response, immune activation and extracellular matrix (ECM) remodeling.

 Immunofluorescence results further confirmed that the hydrogel can downregulate the expression of pro-inflammatory factors (IL-6, TNF-α) and M1 macrophage markers (CD86), and upregulate anti-inflammatory factors (IL-10), M2 markers (CD206), as well as pro-angiogenic and matrix remodeling-related proteins (CD31, VEGF, COL-1), thereby shifting the wound microenvironment from a pro-inflammatory state to a pro-repair state.

In vitro and in vivo biosafety assessments are performed to verify its clinical translation potential. In vitro CCK-8 assays and Live/Dead staining indicated that PIM-NS and the composite hydrogel possess favorable cytocompatibility toward NIH-3T3 cells (cell viability nearly 100%). Hemolysis tests and H&E staining of major organs (heart, liver, lung, kidney) showed that the material has no obvious hematotoxicity or systemic toxicity.

In summary, the lignin-derived poly(phenol-imidazole) nanosheets proposed in this study provide a new paradigm for fabricating multifunctional hydrogel dressings. By breaking the trade-off between mechanical performance and bioactivity of traditional soft tissue materials, synergistic therapy combining antibacterial, antioxidant, anti-inflammatory and tissue regeneration-promoting effects for infected diabetic wounds is achieved. This work offers important guidance for the biomedical applications of next-generation "multitask" nanofillers.

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