Self-immolative hydrogen sulfide and ciprofloxacin co-delivery nanosheets for enhanced treatment of bacterial keratitis

APN-activated self-immolative nanoantibiotic was developed. • H 2 S/Cip co-delivery enabled synergistic anti-inflammatory/antibacterial effects. • The corneal repair from bacterial keratitis was significantly accelerated. Pseudomonas aeruginosa (PA)-induced bacterial keratitis represents one of the most severe corneal infections usually accompanied by prominent inflammatory infiltration. Clinical fluoroquinolone-based therapies yield unfavorable therapeutic outcomes due to the insufficient ocular bioavailability and compromised anti-inflammatory efficacy. In the present work, we report a molecularly engineering strategy to conjugate ciprofloxacin (Cip) with a self-immolative carbonyl sulfide (COS)/hydrogen sulfide (H 2 S) donating motif. The resulting prodrug (termed ASCip) could spontaneously self-assemble into nanosheets in aqueous solution, thereby improving ocular surface retention and drug bioavailability. Importantly, ASCip could be specifically activated by aminopeptidase N (APN), which is overexpressed at the inflammatory sites, enabling the controlled and simultaneous release of Cip and H 2 S, to realize antibacterial and anti-inflammatory effects. In vitro evaluations of this carrier-free nanoantibiotic revealed potent antibacterial activity against PA upon APN activation, favorable biocompatibility, and significant anti-inflammatory effects via modulating the inflammatory mediators and promoting macrophage polarization towards the anti-inflammatory M2 phenotype. In a murine model of PA-infected keratitis, the nanoantibiotic efficiently eradicated pathogens, attenuated ocular inflammation, and remarkably accelerated corneal repair, providing a promising strategy to improve the efficacy of fluoroquinolone-based therapies against bacterial keratitis. More importantly, the strategy developed provides a versatile way to co-deliver COS/H 2 S with other functional motifs. The Cip prodrug ASCip could self-assemble into well-defined nanoantibiotics to enhance ocular retention. Upon APN activation, a spontaneous self-immolative reaction could be triggered to co-deliver H 2 S and Cip simultaneously, enabling synergistic anti-inflammatory and antibacterial effects that promote corneal repair in bacterial keratitis. Download: Download high-res image (114KB) Download: Download full-size image