A promising strategy for ocular noninvasive protein delivery: The case in treating corneal neovascularization

Current clinical treatment of corneal neovascularization (CNV), a leading cause of visual impairment worldwide, by a class of glucocorticoids suffers from the ineffective and numerous adverse effects. Bevacizumab (Beva), an anti-neovascularization protein, is a promising therapeutic option but limited by subconjunctival injection due to its poor penetration across ocular bio-barriers, which significantly reduces patient compliance and increases the risk of infection. Herein, a CmA@Beva nanomedicine was developed, based on the co-assembly of novelly designed peptide, (Cysteine-Histidine-Arginine)3, with Beva in the presence of Zn²⁺. The conditions for the formation of CmA and encapsulation of Beva in CmA were optimized, and the pH-responsive release of Beva and the protective effects of CmA@Beva on Beva were explored. In vitro and in vivo studies showed CmA@Beva exhibited good biocompatibility and demonstrated notable improvements in Beva retention time in the anterior eye segment. CmA@Beva eye drops could overcome corneal bio-barriers by opening ocular surface tight junctions and the endocytosis-lysosomal escape pathway, which together resulted in a therapeutic outcome on rat CNV superior to subconjunctival injection. The present study contributes to the development of a noninvasive protein drug delivery strategy for the treatment of CNV or other diseases of the eye anterior segment.

Statement of significance

Corneal neovascularization (CNV) has been recognized as the leading cause of vision impairment globally, affecting approximately 1.4 million people each year. Protein drugs have shown high specificity and low side effect in disease treatment compared to small molecule drugs. However, limited ability to cross ocular barriers remain a big challenge. Here, a nanomedicine (CmA@Beva) was employed to address this issue through exampling on an anti-neovascularization protein, bevacizumab (Beva). CmA@Beva enhances retention on the ocular surface and effectively delivers Beva across the epithelial barrier, and thus is much more effective than the commonly used subconjunctival injections used for treatment in the clinic. This may be a good strategy for non-invasive delivery of protein drugs for the treatment of anterior segment diseases.