Rapamycin-loaded chitosan functionalized poly (lactic-co-glycolic acid) (PLGA) nanoparticles for potential wet age-related macular degeneration treatment: an in vivo study

Wet age-related macular degeneration (Wet AMD) is a major cause of vision loss and has been linked to abnormal choroidal neovascularization (CNV). Current therapies require frequent intravitreal injections, which leads to poor patient adherence. Herein, this study was designed to investigate rapamycin-loaded chitosan-coated poly(lactic-co-glycolic acid) nanoparticles, which represent a sustained-release drug delivery system for wet AMD. The Rap@CS/PLGA NPs were synthesized using emulsion solvent evaporation, followed by coating with chitosan. The obtained Rap@CS/PLGA NPs exhibited a size of 265.9 ± 6.30 nm and encapsulation efficiency (EE) of 60.30 ± 1.20%. The drug release profile showed a biphasic pattern with reduced initial burst release (6 ± 0.6%) followed by sustained release (46 ± 4.1%) over 72 h, which indicates improved delivery control. In vitro cytotoxicity on ARPE and HUVEC cells showed minimal toxicity, with more than 85% viability at dosages up to 100 μg/mL. In vivo anti-angiogenic assays using the chick chorioallantoic membrane (CAM) model showed that the Rap@CS/PLGA group (13 ± 3 vessels) significantly reduced the vessel formation vs Rap (26 ± 2 vessels), confirming superior anti-angiogenic effects. Moreover, the laser-induced CNV mouse model, Rap@CS/PLGA NPs, significantly reduced levels of inflammatory cytokine (TNF-α and IL-6) and restored antioxidant enzyme (SOD, CAT). This showed that protection against oxidative stress in CNV-affected tissue promotes angiogenic gene expression (VEGFA, CCL2), while preserving retinal structure. These findings propose that Rap@CS/PLGA NPs can effectively and control drug delivery for wet-AMD with long-lasting efficacy.