C-di-GMP@ZIF-8 nanocomposite injectable hydrogel based on modified chitosan and hyaluronic acid for infected wound healing by activating STING signaling

The treatment of infected wounds relies on antibiotics; however, increasing drug resistance has made therapeutic processes more difficult. Activating self-innate immune abilities may provide a promising alternative to treat wounds with bacterial infections. In this work, we constructed an immunogenic injectable hydrogel crosslinked by the Schiff base reaction of carboxymethyl chitosan (NOCC) and aldehyde hyaluronic acid (AHA) and encapsulated with stimulator of interferon genes (STING) agonist c-di-GMP loaded ZIF-8 nanoparticles (c-diGMP@ZIF-8). Nanocubic ZIF-8 was screened as the most efficient intracellular drug delivery vector from five differently-shaped morphologies. The NOCC/AHA hydrogel released c-di-GMP@ZIF-8 more quickly (43 %) in acidic environment (pH = 5.5) of infected wounds compared with 34 % in non-infected wound environment (pH = 7.4) at 96 h due to pH-responsive degradation performance. The released c-di-GMP@ZIF-8 was found to activate the STING signaling of macrophages and enhance the secretion of IFN-(3, CCL2, and CXCL12 5.8-7.6 times compared with phosphate buffer saline control, which effectively inhibited S. aureus growth and promoted fibroblast migration. In rat models with infected wounds, the c-di-GMP@ZIF-8 nanocomposite hydrogels improved infected wound healing by promoting granulation tissue regeneration, alleviating S. aureus-induced inflammation, and improving angiogenesis. Altogether, this study demonstrated a feasible strategy using STINGtargeted and pH-responsive hydrogels for infected wound management.