Sulfhydryl-modified nanocarriers enhance corneal retention and ocular anti-inflammatory efficacy in dry eye therapy.

Abstract

Despite great advances in nanomedicine for targeted drug delivery, the role of nanoparticle (NP) surface chemistry in optimizing ocular therapeutics remains underexplored. Here, we employ a library of DSPE-PEG polymeric nanocarriers functionalized with distinct surface groups (-NH₂, -CH₃, -COOH, -Mal, -SH, -OH) to elucidate the effect of surface chemistry on ocular drug delivery. Among these, sulfhydryl-modified NPs (NP-SH) demonstrated higher cellular uptake across diverse cell types, including dendritic cells, macrophages, tumor cells and corneal epithelial cells, via interactions with membrane proteins rather than classical endocytic pathways. Based on this discovery, the immunosuppressant drug FK506 is encapsulated into NP-SH nanocarrier (FK506@NP-SH) for dry eye therapy. In vitro, FK506@NP-SH exhibits potent anti-inflammatory and anti-apoptotic effects, suppressing key mediators of ocular inflammation such as TNF-α and IL-6, as well as apoptosis. In vivo, FK506@NP-SH achieves prolonged corneal retention and significantly restores tear production, epithelial integrity, and goblet cell density in a murine dry eye model. Mechanistic studies show that NP-SH-mediated FK506 inhibition of NF-κB and MAPK signaling pathways, while comprehensive biosafety assessments confirmed minimal ocular irritation and systemic toxicity. This work provides an effective strategy for rational surface chemistry design to overcome biological barriers in drug delivery. STATEMENT OF SIGNIFICANCE: This study demonstrates that sulfhydryl-modified nanocarriers (NP-SH) enhance corneal retention and cellular uptake, improving FK506 delivery for dry eye therapy. NP-SH suppresses inflammation and apoptosis via NF-κB/MAPK pathways, restoring tear production and epithelial integrity with high biosafety. This work proposes a rational surface chemistry design to address ocular delivery challenges.