Near-infrared-triggered in situ gelation of indocyanine green-upconversion nanocomposite hydrogel for combating refractory keratitis via synergistic antimicrobial therapy and corneal repair

Refractory infectious keratitis presents significant therapeutic challenges due to persistent microbial infections, rising antimicrobial resistance, and the limited precorneal bioavailability of conventional eye drop treatments. While photothermal (PTT) and photodynamic therapies (PDT) offer promising energy-based alternatives, their clinical application is limited by the shallow tissue penetration of visible light and rapid clearance from the ocular surface. Here, we report an integrated near-infrared (NIR)-triggered nanocomposite hydrogel platform (GUCNI) that combines mesoporous silica-coated upconversion nanoparticles (UCNPs@mSiO 2 ), indocyanine green (ICG), and photocrosslinkable gelatin methacrylate (GelMA) to address these convergent clinical challenges. Under a single 808 nm NIR irradiation, this system enables simultaneous in situ gelation for enhanced precorneal retention and spatiotemporally controlled synergistic PTT/PDT. The mesoporous nanoconfinement strategy effectively suppresses ICG aggregation-induced quenching and photobleaching, substantially enhancing photostability and therapeutic efficacy. In refractory bacterial keratitis models, GUCNI demonstrated superior antimicrobial efficacy through combined photothermal and photodynamic mechanisms, achieving complete pathogen eradication while suppressing inflammatory spread and promoting accelerated corneal repair. Transcriptomic analysis confirmed its dual therapeutic action through modulation of host defense pathways (inflammatory chemotaxis, phagocytosis) and tissue regeneration mechanisms (cell adhesion, extracellular matrix remodeling). With its integrated antimicrobial, anti-inflammatory, and pro-repair capabilities delivered via a clinically accessible workflow, GUCNI represents a promising next-generation therapeutic strategy for refractory infectious keratitis. A near-infrared-responsive nanocomposite hydrogel (GUCNI) was engineered by integrating upconversion nanoparticles (UCNPs@mSiO 2 ), indocyanine green (ICG), and photocrosslinkable gelatin (GelMA), leveraging NIR-triggered in situ gelation to enable spatiotemporally controlled synergistic photothermal/photodynamic therapy and sustained drug retention for refractory keratitis treatment, achieving complete bacterial eradication and expedited corneal ulcer repair.