Feedback-regulated 3D-printed hydrogel micropatch for integrated therapy of fungal keratitis

Abstract

Rationale Fungal keratitis remains clinically challenging due to limited drug bioavailability, frequent dosing, reactive oxygen species (ROS)-mediated stromal damage, perforation risk, and bacterial coinfection. In the study, we developed a feedback-regulated multifunctional corneal micropatch (MFCP) via 3D printing for the treatment of fungal keratitis. Methods The dual-network hydrogel micropatch comprises an ROS-responsive hydrogel (RRH), voriconazole-loaded F127DA micelles (VCZ-F127DA), and gatifloxacin-loaded cerium metal-organic frameworks (GAT-MOFs). We characterized its physicochemical properties and evaluated its biocompatibility, corneal healing capacity, ROS scavenging activity, and antimicrobial performance. Histological staining, cytokine assays, and transcriptomic sequencing were used to assess its therapeutic efficacy in a mouse model of fungal keratitis. Results MFCP exhibits tunable curvature, high transparency, and mechanical properties matching those of the cornea, along with good biocompatibility. High ROS level can accelerate breakdown of the micropatch and promote drug release, generating strong synergistic antifungal and antibacterial activities. The released GAT-MOFs scavenge excessive ROS, forming a negative feedback loop. In the mouse model of fungal keratitis, MFCP mitigates corneal infection, lowers proinflammatory cytokines, and accelerates tissue repair, with therapeutic efficacy superior to that of voriconazole eye drops. Transcriptomic analysis reveals suppression of NF-κB-mediated inflammatory signaling and upregulation of corneal regenerative pathways after treatment with MFCP. Conclusion These findings demonstrate that MFCP represents a viable therapeutic option for fungal keratitis.