A Single-Component Dual Donor Enables Ultrasound-Triggered Co-release of Carbon Monoxide and Hydrogen Sulfide

The development of dual gasotransmitter donors can not only provide robust tools to investigate their subtle interplay under pathophysiological conditions but also optimize therapeutic efficacy. While conventional strategies are heavily dependent on multicomponent donors, we herein report an ultrasound-responsive water-soluble copolymer (PSHF) capable of releasing carbon monoxide (CO) and hydrogen sulfide (H2S) based on single-component sulfur-substituted 3-hydroxyflavone (SHF) derivatives. Interestingly, sulfur substitution can not only greatly improve the ultrasound sensitivity but also enable the co-release of CO/H2S under mild ultrasound irradiation. The co-release of CO/H2S gasotransmitters exerts a bactericidal effect against Staphylococcus aureus and demonstrates anti-inflammatory activity in lipopolysaccharide-challenged macrophages. Moreover, the excellent tissue penetration of ultrasound irradiation enables the local release of CO/H2S in the joints of septic arthritis rats, exhibiting superior therapeutic efficacy without the need for any antibiotics. Sulfur-substituted 3-hydroxyflavone was successfully developed as a single-component ultrasound-responsive dual donor of carbon monoxide (CO) and hydrogen sulfide (H2S). The co-release of CO/H2S gasotransmitters under mild ultrasound irradiation shows synergistic antibacterial and anti-inflammatory activities, exhibiting unique therapeutic potential and outperforming conventional antibiotic treatment in a murine septic arthritis model.image

Automated summary

This study developed a single-component ultrasound-responsive dual gasotransmitter donor that can release carbon monoxide (CO) and hydrogen sulfide (H2S) simultaneously, showing synergistic antibacterial and anti-inflammatory activities. It exhibits unique therapeutic potential and outperforms conventional antibiotic treatment.