Annular microneedles with cationic SLNs enable minimally invasive sustained co-delivery of resveratrol and conbercept...

Repeated intravitreal injections of anti-vascular endothelial growth factor agents for choroidal neovascularization (CNV) impose significant patient burden, increase the risk of ocular complications, and lead to poor compliance. To address these limitations, we developed a transscleral, sustained-release platform aiming to enable single-administration combination therapy targeting multiple pathological pathways while reducing injection frequency and avoiding intravitreal puncture. Cationic solid lipid nanoparticles (Res/Conb-SLNs) were fabricated via thin-film ultrasonication and electrostatic adsorption to co-encapsulate resveratrol (Res) and conbercept (Conb). These were integrated into hyaluronic acid-based annular dissolvable microneedles (Res/Conb-SLNs@MN, 500 μm height) designed to target the suprachoroidal space (SCS) while avoiding the optical axis. The system achieved biphasic sustained release over 48 h (>80% Res, >90% Conb) and demonstrated rapid microneedle dissolution (<30 s) with complete micropore closure within 24 h. Enhanced cellular uptake, potent antioxidant activity, and significant inhibition of endothelial cell migration/tube formation were observed. Intraocular pharmacokinetic experiments confirm that this Res/Conb-SLNs@MN achieved SCS-targeted accumulation with significantly extended posterior segment retention. In a laser-induced rat CNV model, Res/Conb-SLNs@MN delivered therapeutic agents efficiently to the retina-choroid region, significantly suppressing CNV leakage, reducing neovascularization, and attenuating inflammatory cell infiltration. No changes in intraocular pressure or retinal histology were observed over 42 days. Moreover, the safety of repeated microneedle administration was good. This annular microneedle-nanocomposite system enables transscleral, sustained, and targeted co-delivery to the posterior segment without the need for intravitreal puncture, offering a transformative strategy to replace frequent intravitreal injections with a synergistic, patient-compliant approach for neovascular retinal diseases.