Abstract
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.
Data availability
RNA-Seq data generated in this work have been deposited in the NCBI Gene Expression Omnibus database under the accession code PRJNA1298406. All data needed to evaluate the conclusions in this work are presented in the manuscript and/or Supplementary Materials. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant nos. 52293382 to F.J.X., 52303172 to K.Z., 52361165659 to N.Z., and 52221006 to F.J.X.), Beijing Natural Science Foundation (grant no. 2262072 to K.Z.) and the Fundamental Research Funds for the Central Universities (JD2518 to K.Z.). All animal experiments in this study were approved by the Animal Ethics Committee of Capital Medical University.
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Conceptualization: Y.Y., K.Z. Methodology: Y.Y., Y.W. Investigation: Y.Y., K.Z., visualization: Y.Y. Supervision: K.Z., Y.L., N.Z., and F.J.X. Writing-original draft: Y.Y. Writing-review and editing: K.Z., N.Z., and F.J.X.
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Nature Communications thanks Hongzhe Sun, who co-reviewed with Chenyuan Wang, Min Lu and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Ye, Y., Zhang, K., Wang, Y. et al. Biomimetic metal-drug coordination nanoplatform to counteract drug resistance in Pseudomonas aeruginosa via energy disruption. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69712-6
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DOI: https://doi.org/10.1038/s41467-026-69712-6
