Sulfonamide antibiotics, though clinically essential, are associated with severe systemic toxicity and hypersensitivity reactions. To address this, we developed ultrasound (US)-activated nanoparticles for selective antibacterial therapy. The prodrug SMX-N₃—synthesized by azido-masking of the aromatic amine in sulfamethoxazole (SMX)—was co-loaded with a sonosensitizer (riboflavin tetrabutyrate, TBR) into antibacterial peptide (HHC-10)-modified poly(ethylene glycol)- b -poly( D, l -lactide) nanoparticles (HPP (SMX-N 3 + TBR)). This design enables the selective reduction of SMX N₃ to the active form SMX at the infected site through TBR-mediated reactions under low-intensity US stimulation. The HPP carrier enhanced bacterial membrane targeting via HHC-10, thereby improving drug accumulation. In vitro, HPP(SMX-N₃ + TBR) combined with US achieved >90% antibacterial efficacy against S. aureus and E. coli at 20 μg∙mL −1 . In vivo, US irradiation increased wound-site SMX concentrations by 6.14-fold over non-targeted controls, reducing systemic toxicity (no weight loss or hepatorenal damage vs. free SMX). In infected rat wounds, this strategy effectively eliminated bacteria, suppressed pro-inflammatory cytokines, promoted angiogenesis, and accelerated collagen deposition, achieving 97.49% wound closure. This study establishes an azido-prodrug platform with precise antibacterial activity. • Ultrasound-activated azido-masked sulfamethoxazole targets bacteria selectively • Antibacterial peptide enhances bacterial targeting and drug accumulation • Selective sulfamethoxazole release at infection sites reduces systemic toxicity • Achieves >90% antibacterial efficacy and promotes wound healing • Platform enables precise, externally controlled antibacterial therapy
Sun et al. (Sun,) studied this question.