On-demand dual-stimuli-responsive hydrogels for localized and sustained delivery of MP-L [I5R8] to treat bacterial wound infections

Abstract

This study presents the development of two novel injectable dual-responsive polyanionic hydrogels (DRPHs) based on N-isopropylacrylamide (NIPAM), incorporating carboxylic acid comonomers for temperature- and pH-responsive drug release. These hydrogels were designed for the sustained and localized delivery of the antimicrobial peptide MP-L [I5R8], targeting multidrug-resistant bacteria (MDRB) in wound infections. The physicochemical characterization confirmed polymer formation and comonomer integration through Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). Rheological analysis demonstrated a temperature-dependent sol-gel transition at ∼35°C, making the hydrogels suitable for in situ gelation at physiological conditions. The hydrogels exhibited tunable swelling behavior and a controlled dual-phase release profile of MP-L [I5R8], ensuring both immediate bactericidal activity and prolonged antimicrobial effect. In vitro assays confirmed sustained antimicrobial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa, while biocompatibility tests validated their safety for biomedical applications. An in vivo diabetic wound infection model demonstrated rapid infection clearance, enhanced wound healing, and organized tissue regeneration following treatment with MP-L [I5R8]-loaded DRPHs. These results highlight the potential of dual-stimuli-responsive hydrogels as a next-generation antimicrobial delivery platform for the treatment of chronic infected wounds, such as diabetic foot ulcers.