Synergistic sonodynamic and ion-interference therapy effectively treats osteomyelitis and promotes neural and osteogenic regeneration.

Abstract

Osteomyelitis remains a formidable clinical challenge due to incomplete bacterial clearance, persistent inflammation, and impaired bone regeneration, while the overuse of antibiotics accelerates the emergence of multidrug resistance. To address these issues, we developed a multifunctional nanoplatform based on gallium-doped riboflavin (Ga-VB₂), which integrates sonodynamic therapy with ion interference for comprehensive osteomyelitis management. Theoretical calculations indicate that Ga doping polarizes VB₂ into a donor-acceptor system, strengthening water adsorption and charge separation to underpin its enhanced sonodynamic activity. Ga³⁺ competitively binds to iron-dependent enzymes and proteins, but, unlike Fe³⁺, remains a stable redox-inert trivalent ion, thereby disrupting essential bacterial metabolic processes. Antibacterial assays confirmed that Ga doping conferred intrinsic antibacterial activity, which was further significantly amplified under ultrasound irradiation. Consistently, prokaryotic RNA-seq analysis revealed a global transcriptional reprogramming upon Ga-VB₂ activation by ultrasound, characterized by pronounced downregulation of energy metabolism-related genes and concomitant upregulation of stress-adaptation pathways. Beyond antibacterial efficacy, both in vitro and in vivo experiments demonstrated that Ga-VB₂ exhibits excellent biocompatibility, while simultaneously alleviating inflammation, promoting bone regeneration, and supporting neural repair. Collectively, this work highlights Ga-VB₂ as a multifunctional therapeutic platform that synergizes antimicrobial activity with enhanced bone regeneration, offering a promising strategy for the treatment of drug-resistant osteomyelitis and related bone defects.