Thermal‐Cascade Multifunctional Therapeutic Systems for Remotely Controlled Synergistic Treatment of Drug‐Resistant Bacterial Infections

Abstract Antimicrobial therapy remains one of the major global challenges, particularly in the absence of effective treatment strategies for drug‐resistant bacteria. In this study, a comprehensive treatment approach is proposed for drug‐resistant bacterial wound infections based on the development of thermal‐cascade multifunctional therapeutic systems (MTSs), spanning from the design of functional nanoscale materials to macroscopic smart hydrogel. Within the MTSs, functional antibiotic‐loaded hybrid nanoclusters enable targeted therapeutic delivery and synergistic mild hyperthermia‐antibiotic treatment, strongly suppressing drug‐resistant bacteria while demonstrating excellent biocompatibility with normal cells and tissues. Furthermore, near‐infrared irradiation can trigger the photothermal effects of hybrid nanoclusters to induce gelation of thermal‐sensitive hydrogel, forming MTSs to serve as highly adaptable, drug‐enriched protective dressings for infected wounds. Both in vitro and in vivo results substantiate that MTSs enhance the bioavailability of therapeutic agents (including bacterial internalization and tissue penetration), exert synergistic effects to completely eradicate drug‐resistant bacteria, promoted wound healing and revascularization, and demonstrate excellent biocompatibility. This work offers an innovative demonstration to address drug‐resistant bacterial infections through the advancement of sophisticated material systems.