Combined delivery of small molecule and protein drugs as synergistic therapeutics for treating corneal neovascularization by a one-pot coassembly strategy

Combined drug administration is a potential strategy to increase efficacy through therapeutic synergy. Small molecule drugs and protein drugs are the two most popular kinds of drugs in medicine. However, efficiently encapsulating these two drugs still have key challenges due to their distinct properties (molecular weight, hydrophilicity, chemical groups, etc.), weak ability to penetrate through various biobarriers (cell membrane, endosome escape, tissue barriers dependent on the method of administration, etc.) and the easy deactivation of protein drugs during the construction of carrier and delivery process. Here, we utilize the hexahistidine-metal assembly (HmA), which can encapsulate a wide spectrum of drugs with high loading efficiency, to coencapsulate Dexp (a small molecule drug) and BVZ (protein drug) by a one-pot coassembly strategy. Our data demonstrated that Dexp and BVZ were coloaded into Dexp&BVZ@HmA with high efficiency, while the bioactivity of BVZ was well-maintained. Most importantly, when evaluating the therapeutic outcomes of drugs@HmA in a corneal neovascularization (CNV) model in vitro and in vivo, the combination group presented overwhelming efficacy compared to the monotherapy group. This strategy offers a platform to codeliver protein and small drugs and has the potential for treating anterior segment diseases as well as other diseases that need combination therapy.