Engineered nanoparticles for subconjunctival delivery to the retinal pigment epithelium: A multi-target therapy for dry AMD

Dry age-related macular degeneration (dAMD) is a leading cause of irreversible blindness, driven by oxidative stress-induced retinal pigment epithelial (RPE) cell degeneration. Existing therapies suffer from poor bioavailability and insufficient multi-pathway modulation. To address this, we developed P(R)/T-Lf nanoparticles, a subconjunctivally administered nanotherapy co-loaded with resveratrol (Res) and dual-functionalized with trimethyl chitosan (TMC) and lactoferrin (Lf). The P(R)/T-Lf NPs exhibited: (1) prolonged ocular retention via TMC-mediated mucoadhesion and enhanced RPE targeting through Lf receptor binding; (2) sustained Res release over 35 days, effectively scavenging reactive oxygen species and inhibiting ferroptosis by downregulating NOX2, ACSL4, and COX2 while restoring GPX4; (3) superior therapeutic outcomes in NaIO₃-induced dAMD models, preserving retinal morphology and function. Comparative studies demonstrated that P(R)/T-Lf NPs outperformed non-targeted controls. This nanoplatform provides a translation-ready strategy to concurrently tackle oxidative stress, inflammation, and ferroptosis via sustained, targeted delivery, representing a transformative approach for dAMD therapy.