Enhancing Antibacterial Activity of Glabridin by an Ultrasound‐Triggerable Nanoformulation

Plant-derived compounds are widely used to treat bacterial infections. However, most of them exhibit poor antibacterial activity, particularly against Gram-negative bacteria, and this is further compounded by dose-limiting toxicity. Herein, we present that the antibacterial activity of a plant component, glabridin (GLA), can be enhanced by an ultrasound-triggered perfluorooctyl bromide (PFOB)-liposome nanoformulation, and the biocompatibility thereby improves. When combined with ultrasound, PFOB serves as seed bubbles that generate mechanical forces, inducing liposome rupture and releasing GLA. Meanwhile, the sublethal membrane perturbation caused by US and PFOB synergizes with a low dosage of GLA, resulting in remarkable bactericidal efficacy against both E. coli and P. aeruginosa, with no resistance developing after 30 passages. The irreversible damage to the membrane triggers metabolic collapse in the treated E. coli, as demonstrated by non-targeted metabolomics analysis. We further validated the efficacy of our nanoformulation in treating E. coli-infected wounds in vivo by reducing bacterial load, accelerating healing, and mitigating excessive inflammation. Our work suggested an approach to strengthen the applicability of plant extracts in combating antibiotic resistance.