Ros-responsive hydrogel with size-dependent sequential release effects for anti-bacterial and anti-inflammation in diabetic wound healing

Bacterial infection and the resulting inflammatory cascade are key factors hindering diabetic ulcers healing. The essential prerequisites for promoting diabetic ulcer healing are to sequentially achieve rapid sterilization, prevent reinfection, and modulate the inflammatory response. Inspired by the size-dependent sequential toxin release behavior of "Malaysian exploding ant", we develop a ROS-responsive "exploding hydrogel" (E -gel) with size-dependent sequential release effects, which sequentially performs photothermal sterilization, persistent antibacterial activity, and immune regulation. Specially, polyhexamethylene guanidine (PHMG, P) and mesoporous polydopamine nanoparticles loaded with alpha-lipoic acid (alpha-LA@MPDA NPs, LD) were encapsulated into sulfhydryl-modified hyaluronic acid (HA-SH) through disulfide bonds to form a PLD/E-gel. The high temperatures generated by the photothermal effects of MPDA can kill over 90 % of bacteria within 10 min. During the swelling period of PLD/E-gel, PHMG diffuses out and effectively prevents the wound from re-infection. Along with the degradation of PLD/E-gel, submicron-sized alpha-LA@MPDA NPs are released from the cross-linked network to scavenge excessive ROS and modulate the inflammatory cascade. Animal experiments shows that PLD/E-gel accelerates the healing of infected diabetic wounds in SD rats by rapidly killing bacteria, inhibiting bacterial recolonization, relieving wound inflammation, and facilitating collagen deposition. To sum up, PLD/E-gel has a great application potential for diabetic wound healing.