A neutrophil membrane-biomimetic drug delivery system enhances the antifungal and anti-inflammatory efficacy of natamycin for fungal keratitis

Fungal keratitis (FK) is a potentially blinding infectious corneal disease. The invasion of fungi into corneal tissue and the resulting inflammatory response primarily drive the rapid corneal damage. Although natamycin (NAT) is the first-line treatment for FK, its clinical efficacy faces challenges due to several drawbacks, including poor anti-inflammatory effects, low water solubility, frequent dosing requirements, and considerable ocular surface irritation. In our study, we aimed to develop a novel neutrophil membrane-biomimetic drug delivery system to solve these challenges of NAT and and enhance its antifungal and anti-inflammatory efficacy in FK. The neutrophil membranes from β-glucan-stimulated (βNM) cells were used to construct a novel biomimetic delivery system termed G-NAT@βNM by encapsulating NAT-loaded gelatin nanoparticles (G-NAT). The novel G-NAT@βNM system exhibited enhanced ability to inhibit Aspergillus fumigatus (A. fumigatus) growth, disrupted fungal cell walls and membranes, and markedly reduced spore adhesion and biofilm formation. In vivo, G-NAT@βNM more substantially alleviated corneal lesions, reduced fungal load, limited inflammatory cell infiltration, and suppressed key inflammatory cytokines. G-NAT@βNM also significantly decreased inflammatory cytokine levels stimulated by A. fumigatus in vitro, confirming its anti-inflammatory activity. These findings indicate that the neutrophil membrane-biomimetic drug delivery system (G-NAT@βNM) offers an innovative and effective therapeutic system for FK.