A multifunctional nanobooster to restore ceftazidime susceptibility in mucoid Pseudomonas aeruginosa.

Mucoid Pseudomonas aeruginosa (m.PAE) presents a major clinical challenge due to its high resistance to ceftazidime (CAZ), a cornerstone antibiotic. This resistance is orchestrated through three barriers, including the formation of an alginate-rich mucoid biofilm that limits drug penetration, upregulated efflux pumps such as MexAB-OprM that reduce intracellular CAZ accumulation, and expression of β-lactamases that hydrolyze CAZ. To address these barriers simultaneously, we engineered a multifunctional nanobooster termed A/C-pAg3PO4, which integrates a silver phosphate nanoparticle (NAg3PO4) core for bacterial disruption, a carboxyl-PEG coating (pAg3PO4) to improve biofilm penetration, and dual co-loading of avibactam (AVB) to inhibit β-lactamase and carbonyl cyanide m-chlorophenylhydrazone (CCCP) to block efflux pumps. In vitro, A/C-pAg3PO4 showed potent antibacterial efficacy, penetrated mucoid biofilms efficiently, and restored bacterial susceptibility via metabolic reprogramming. In murine models of acute pneumonia and lethal sepsis, it markedly reduced bacterial load, mitigated inflammatory damage, and achieved complete survival with no evident toxicity. Our work thus provides a promising strategy to overcome m.PAE resistance to CAZ by concurrently targeting its key defensive mechanisms.