Synchronous Metabolic Interference and Immune Reprogramming by a Self-Assembled Bismuth–Phenolic Nanoparticle against Pseudomonas aeruginosa -Induced Infections

Abstract

Effective eradication of Pseudomonas aeruginosa (P. aeruginosa) infection remains challenging due to its multifaceted antibiotic resistance mechanisms and biofilm-associated protection. Furthermore, inflammatory dysregulation within the infected microenvironment compromises both antibacterial efficacy and tissue repair. Therapeutic strategies capable of simultaneously eliminating pathogens and restoring microenvironmental homeostasis are therefore highly desirable. Herein, we report a bismuth-phenolic nanoparticle (BAQ NP) for synergistic antibacterial and immunomodulatory therapy of bacterial infections. BAQ NPs are synthesized via the self-assembly of phenylboronic acid-modified azithromycin (P-AZM), quercetin (Qu), and bismuth potassium citrate (BPC) through the formation of metal-phenolic networks and dynamic boronate ester linkages. BAQ NPs exhibit effective bacterial adhesion and enable pH-responsive release of bioactive components. Meanwhile, BAQ NPs disrupt bacterial iron homeostasis, suppress electron transport, restrict energy supply, and inhibit efflux pump function, thereby markedly potentiating the antibacterial efficacy of AZM. Concurrently, BAQ NPs promote macrophage polarization toward a reparative phenotype and alleviate inflammatory dysregulation, facilitating tissue recovery. The therapeutic efficacy of BAQ NPs was further demonstrated in murine pneumonia and diabetic infected wound models.