Multifunctional injectable hydrogel with self-supplied H₂S release and bacterial inhibition for the wound healing with enhanced macrophages polarization via interfering with PI3K/Akt pathway

Hydrogen sulfide (H₂S) gas therapy is beneficial for accelerating wound healing and alleviating the inflammatory process, but is seriously hindered by insufficient delivery and unsustainable release in vivo. This study presents a multifunctional injectable hydrogel, OC@ε-PL-SATO, composed of oxidized hyaluronic acid and N-acetylcysteine (NAC) as an initiator, carboxymethyl chitosan and S-aroylthiooxime modified ε-Poly-(L-lysine) (ε-PL-SATO). ε-PL-SATO is a NAC-responsive H₂S donor. OC@ε-PL-SATO hydrogel is designed for the desired wound healing process, with rapid gelation (<30 s) and a sustained H₂S release. After mixing and gelling, H₂S could be long-term released from the hydrogel and effectively drives macrophages toward M2 polarization, thereby ameliorating the inflammatory response. Revealed by transcriptome analysis, the underlying mechanism is that OC@ε-PL-SATO hydrogel releasing H₂S inhibits LPS-mediated inflammatory responses in RAW264.7 cells by interfering with phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling and NF-κB activation. Furthermore, the OC@ε-PL-SATO hydrogel effectively eliminates the bacterial burden and alleviates the accompanying inflammation in a rat model of cutaneous wound infection. Importantly, the sustained generation of H₂S gas significantly promotes angiogenesis and collagen deposition, ultimately accelerating the wound repair. In conclusion, this study provides a multifunctional injectable hydrogel with rapid gelatinization and continuous H₂S release for accelerating the infected wound healing.