Highly Efficient Intrastromal Dual-Drug Delivery by a Dissolving Bilayer Microneedle for Synergistic Therapy against Corneal Neovascularization

Corneal neovascularization (CNV) is one of the major causes of vision impairment and blindness worldwide. Efficient intrastromal drug delivery of antiangiogenic agents is a significant challenge due to the presence of various ocular barriers (<i>i.e</i>., tear barrier, corneal epithelial barrier, <i>etc.</i>). Here, we report a rapidly dissolving bilayer microneedle (MN) patch, combining the anti-VEGF antibody (Ava) with an integrin-targeted anti-inflammatory drug (PF-Y-RGD), achieving synergistic therapy for CNV. Equipped with microscale needle tips, the topically applied MN patches reversibly pierce the corneal epithelium to generate microchannels, bypassing the tear/epithelial barrier and facilitating the transport of payload drugs into the stromal layer of the cornea, which significantly enhances drug bioavailability. Such MN patches exhibit biphasic drug release behavior and are also readily applicable and minimally invasive to impart good ocular tolerance. A rabbit model of CNV reveals that the combination of Ava with PF-Y-RGD in such bilayer MN patches robustly inhibits neovascularization and reduces neovascular areas and the expression of various cytokines (<i>i.e</i>., VEGF, TNF-α, IL-1β, MMP-9) in the cornea. As a strategy for efficient intrastromal drug delivery, this study promises an easy and effective way to treat CNV, which may also lead to approaches for curing various ocular disorders.