Macromolecular carrier with long retention and body-temperature triggered nitric oxide release for corneal alkali burn therapy via leptin-related signaling

Corneal injuries, such as alkali burn, are a common ocular trauma worldwide and usually cause corneal opacification and even loss of sight, if without timely treatments. Eye drops have long been regarded as the best media for treating ocular surface diseases. However, their effectiveness was seriously dampened by natural selfcleaning mechanism of the eye. Herein, we designed and prepared polyamino acid-based poly-S-nitrosothiols (PGlu-TEPA-SNAP) as long-acting eye drops to treat corneal alkali burns. The cationic polymeric NO donor demonstrated good retention on the negatively charged surface of cornea without causing obvious biotoxicity. Meanwhile, the polymer can release NO in a temperature-dependent manner, by remaining relatively stable at 4 degrees C and 25 degrees C, while rapidly releasing NO at around 35 degrees C. In vivo study proved that the eye-drop with proper concentration effectively mitigated alkali-induced corneal damage in mice, via leptin related STAT3/MAPK/AKT signaling pathway. It selectively promoted epithelium regeneration without inducing neovascularization by utilization of the difference in cell sensitivity towards NO. Overall, the combined strategy of temperaturedependent drug release and strong retention of carriers can indeed fasten the healing of damaged cornea. It may serve as an inspiration for future NO or leptin-based work for ocular surface therapy.