Application of a novel thermal/pH-responsive antibacterial paeoniflorin hydrogel crosslinked with amino acids for accelerated diabetic foot ulcers healing.

Diabetic foot ulcers (DFUs), a severe and common complication of diabetes, present significant treatment challenges due to the limitations of conventional dressings, such as poor mechanical properties, bioactivity, and limited functionality, which hinder fast and effective wound healing. To address these issues, we developed a novel natural amino acid-based hydrogel loaded with paeoniflorin (PF@PNMA1) and comprehensively evaluated its properties and functions. The nanogel particles (NGs) were synthesized via emulsion polymerization using N-isopropylacrylamide (NIPAM), methacrylic acid (MAA), and chemically modified arginine (MArg). The poly(NIPAM-co-MAA) (PNM) and poly(NIPAM-co-MAA-co-MArg) (PNMA) gels were prepared by functionalizing the NGs with glycidyl methacrylate (GMA). The different concentrations of amino acids were added to explore the optimal mechanical properties of the gel. Through the rheological measurement, we found that PNMA1 gel has good ductile properties with a critical strain up to about 63 %. At the same time, we also verified its antibacterial activity and found that the viability of bacteria decreased to 47.46 % after 3 h. Preliminary tests using network pharmacology and molecular docking confirmed the therapeutic potential of PF for DFUs. The PF@PNMA1 gel demonstrated excellent biocompatibility, and in vivo experiments revealed its effectiveness in promoting angiogenesis and wound healing. After 10 days, the wound healing rate was 25.6 % higher than that of the control group. The PF@PNMA1 shows great potential as an effective therapy for DFUs treatment.