Mannose-modified miR-223 nanoparticles remodel pathological microenvironment to suppress inflammation and angiogenesis for neovascular AMD therapy.

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, with neovascular AMD (nAMD) driven by choroidal neovascularization (CNV), persistent inflammation, and oxidative stress. Although combinatorial strategies targeting these pathological factors hold therapeutic promise, their clinical translation is constrained by the lack of effective delivery systems. In this study, we designed a mannose-functionalized poly(aspartic acid)-based nanocarrier bearing quaternary ammonium and boronic acid groups (MDA/QPABA) for the targeted delivery of microRNA-223 (miR-223). The system exploits charge-driven self-assembly to form stable nanoparticles with high loading efficiency, favorable colloidal stability, and tunable surface properties. The mannose moieties enable specific recognition by mannose receptors on target cells, facilitating cellular uptake and subsequent lysosomal escape. The resulting MDA/QPABA/miR-223 nanoparticles demonstrated pronounced anti-inflammatory, antioxidant, and anti-angiogenic activities in vitro. In a laser-induced CNV mouse model, they effectively reduced inflammatory and angiogenic cytokines, suppressed pathological neovascularization, restored retinal and choroidal structure, and preserved photoreceptor function, with an excellent biosafety. These findings highlight the potential of rationally engineered poly(aspartic acid)-based nanoarchitectures with tailored surface chemistry and biointerfacial properties for multifunctional nucleic acid delivery in nAMD therapy.