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

Abstract

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 Mg²⁺ and Cu²⁺, allowing a synergistic effect of immunomodulation, anti-inflammatory, and angiogenesis during pro-healing process. Under triggering with a low level of exogenous hydrogen peroxide (H₂O₂) 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 H₂O₂ administration, Mg²⁺ 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, Cu²⁺ 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.

Keywords: Anti-infection and pro-healing effects; Drug-resistant bacteria infected wounds; Macrophage reprogramming-angiogenesis; Multifunctional ultrathin medium entropy metal oxides; ROS-based nanocatalytic therapy.