Photothermal-responsive nanocomposite injectable hydrogel capable of programed peroxidase-mimicking catalysis and immunomodulation and revascularization enables efficient drug-resistant bacterial elimination and comprehensive tissue regeneration.

Intractable infected wound caused by drug-resistant bacteria remains a severe healthcare problem. Reactive oxygen species (ROS)-based nanocatalytic therapy (ROS-NT) is harnessed to combat drug-resistant bacterial infection. However, it can also cause immune imbalance and excessive inflammatory responses, postponing subsequent wound healing process. Herein, a multifunctional ultrathin medium entropy metal oxides (UMEMOs)-based photothermal-responsive injectable hydrogel (UMEMOs/PF-MAL) was constructed, which is capable of efficient ROS-producing catalysis, immunomodulation, and revascularization. UMEMOs/PF-MAL can further provide an effective spatiotemporal therapy with programmed anti-infection and pro-healing effects to overcome drug-resistant bacterial infected wound. The incorporation of UMEMOs in injectable hydrogel not only endows UMEMOs/PF-MAL hydrogel with excellent peroxidase (POD)-mimicking activity and near infrared (NIR)-triggered photothermal conversion property, but also significantly improves its sol-gel properties. Moreover, UMEMOs/PF-MAL hydrogel can provide favorable release of Mg and Cu, allowing a synergistic effect of immunomodulation, anti-inflammatory, and angiogenesis during pro-healing process. Under triggering with a low level of exogenous hydrogen peroxide (HO) and NIR irradiation, the photothermal-enhanced POD-like activity of UMEMOs/PF-MAL hydrogel enables efficient catalytic generation of hydroxyl radical (OH) at wound sites, which can easily permeate bacteria due to the local photothermal effect, killing drug-resistant bacteria and destroying biofilms. Following the cessation of HO administration, Mg released from UMEMOs/PF-MAL hydrogel causes the polarization of pro-inflammatory M1 to anti-inflammatory M2 macrophages, thereby reducing the inflammatory response and promoting tissue remodeling. Meanwhile, Cu release boosts angiogenesis, and mild photothermal effect improves local blood oxygen circulation and alleviates inflammation, further accelerating wound healing. Therefore, this work offers a multifunctional UMEMOs/PF-MAL hydrogel with programmed anti-infection and pro-healing effects, achieving an efficient spatiotemporal therapy and the optimum therapeutic effect for drug-resistant bacteria infected wound.