Biomimetic metal-drug coordination nanoplatform to counteract drug resistance in Pseudomonas aeruginosa via energy disruption

The rapid emergence of antimicrobial resistance is a critical global health challenge that renders conventional antibiotics ineffective. Developing innovative strategies to resensitize drug-resistant pathogens to existing antibiotics represents a promising therapeutic approach. Here, we present a biomimetic nanoplatform (Ce-Car@EV NPs) through the rational integration of ginger-derived extracellular vesicles (EVs) and a pH-responsive cerium-carbenicillin coordination nanoparticles (Ce-Car NCPs). This design enables prolonged circulation and targeted degradation in acidic infection sites, releasing Ce⁴⁺ ions and carbenicillin. The released Ce⁴⁺ ions penetrate the bacterial cells, where they disrupt ATP synthesis, impede oxidative phosphorylation, and inhibit the activity of efflux pump. By depleting ATP, blocking efflux pumps, and thereby reversing bacterial resistance, Ce⁴⁺ ions act as a potent adjuvant to carbenicillin. Here we show that this strategy effectively restores carbenicillin efficacy against drug-resistant Pseudomonas aeruginosa both in vitro and in vivo, establishing a therapeutic strategy leveraging metallic adjuvants to counteract antimicrobial resistance.