Synergistic antibiosis with spatiotemporal controllability based on multiple-responsive hydrogel for infectious cutaneous wound healing

Bacterial infection is one of serious problems hindering tissue regeneration, but strategies able to perform proper antibiosis with spatiotemporal controllability to manipulate the local inflammation and immunity for effective healing of infected wound is still a challenge. Herein, we fabricated a smart hydrogel (CNMs@HA-PDA-PL) with multiple responsiveness to near infrared radiation, visible light, hyaluronidase and hydrogen peroxide for promoted healing of the infected wound via controllable anti-bacteria at designed locations and time periods as well as the on-demand regulation of local inflammation and immunity. The hydrogel consists of hyaluronic acid (HA) modified graphitic carbon nitride (g-C₃N₄) microsphere (CNMs), antimicrobial peptides (ε-Poly-L-lysine, ε-PL) and polydopamine (PDA). The PDA framework and CNMs respectively serve as photothermal agent and photodynamic agent to generate heat and radical for instant damage of major bacteria on/surrounding the hydrogel, while the ε-PL is in charge of the sustained antibiosis in long term to eliminate the deep bacteria away from the hydrogel via biochemical process. Once the hydrogel was located at infected area, the over-expressed hyaluronidase and hydrogen peroxide would sequentially spread CNMs and ε-PL to start photodynamic therapy and biochemical therapy in designed range after initial photothermal therapy, resulting in synergistic antibiosis with spatiotemporal controllability. This stepwise anti-bacteria process meanwhile manipulated the local inflammatory microenvironment to promote tissue regeneration, in which the hydrogel gradually performed effective recruitment of inflammatory (M1) macrophages and continuous phenotypic transition of these M1 macrophages toward pro-reparative (M2) macrophages, leading to a rapid healing of the infectious cutaneous wound.