Ultrathin high-entropy hydrotalcites-based injectable hydrogel with programmed bactericidal and anti-inflammatory effects to accelerate drug-resistant bacterial infected wound healing.

Drug-resistant bacteria infected wounds often bring high risks of delayed healing process and even death. Sonodynamic therapy (SDT) can efficiently kill drug-resistant bacteria. However, superabundant reactive oxygen species (ROS) generated during SDT inevitably trigger significant inflammatory responses, hindering tissue remodeling. Herein, we develop intelligent ultrathin high-entropy hydrotalcites (UHE-HTs)-based injectable thermal-responsive hydrogel loaded with nicotinamide mononucleotide (UHE-HTs/PFN), aiming to achieve programmed antibacterial and anti-inflammatory effects. In the early infection stage, sonosensitive UHE-HTs/PFN hydrogel simultaneously can trigger rapid production of singlet oxygen (1O2) under ultrasound and efficient MDR bacterial sterilization. After halting ultrasonic irradiation, oxidoreductase-mimicking catalysis and nicotinamide mononucleotide release of UHE-HTs/PFN hydrogel effectively reduce ROS levels at wound sites, dampening the NF-κB inflammatory pathway. Such inhibited NF-κB expression can not only reduce the production of pro-inflammatory cytokines and inflammatory responses, but also significantly down-regulate the pyroptosis pathways (NLRP3/ASC/Casp-1) and inhibit pyroptosis that leads to inflammation. Moreover, significantly reduced ROS levels and synergistic release of Mg2+ reverse pro-inflammatory immune microenvironment. Both in vitro and in vivo assays demonstrate that UHE-HTs/PFN hydrogel can transform the adverse infected wound environment into a regenerative one by eradicating drug-resistant bacteria, scavenging ROS, and synergistic anti-inflammation. Therefore, this work develop an intelligent UHE-HTs/PFN hydrogel act as a "lever" that effectively achieve a balance between ROS generation and annihilation, rebuilding harmonious bactericidal and anti-inflammatory effects to remedy drug-resistant bacteria infected wound.