Deliver protein across bio-barriers via hexa-histidine metal assemblies for therapy: A case in corneal neovascularization model

Abstract Due to their high specificity and low side effects, protein drugs possess a substantial global market. However, the low bioavailability of protein is still a major obstacle to their expanded applications, which are expected to be answered with proper protein formulations. Taking corneal neovascularization as an example, we demonstrated a co-assembled system of hexa-histidine and Ava (Avastin) with metal ions (HmA@Ava) could across the cornea, the most important bio-barrier during the treatment of most diseases of the anterior segment in clinics. We found that the nanosized HmA@Ava efficiently encapsulated Ava with impressive loading capacity without destroying the bioactivity of Ava and assisted Ava penetration through the corneal barriers to effectively inhibit CNV development in an alkali burn rat model with sustained and pH-dependent Ava release. Our results suggested that the co-assemble strategy of protein and HmA is a proper formulation to protein drugs, with promising penetration ability to deliver protein across bio-barriers, which could open a path for topical administration of protein drugs for treatment of various ocular diseases and hold enormous potential for delivery of therapeutic proteins not only for ocular diseases but also for other diseases that require protein treatment.