Supramolecular Nrf2-activating peptide nanotherapeutics enable deep retinal penetration and RPE targeting for dry age-related macular degeneration.

Dry age-related macular degeneration (AMD) is a leading cause of blindness that currently lacks effective therapies. Restoring redox homeostasis in the retinal pigment epithelium (RPE) via the Keap1-Nrf2 axis offers a compelling precise therapeutic strategy. While peptide-based protein-protein interaction (PPI) inhibitors are highly specific for this axis, the delivery to the deep RPE layer remains a formidable challenge, typically restricted by electrostatic entrapment within the vitreous matrix or limited transretinal penetration. Herein, we developed a novel, mechanism-driven, supramolecular peptide nanotherapeutic (FNBP) engineered to bypass these barriers and reach the RPE layer. Driven by distinct fluorophilic self-assembly, FNBP spontaneously organizes into bio-inert nanostructures that evade vitreous adhesion and exhibit superior transretinal diffusivity and accumulation to the RPE layer. Upon RPE internalization, the assembly leverages its physicochemical properties to trigger efficient cytosolic release, allowing the payload to disrupt the Keap1-Nrf2 interaction, thereby enabling potent Nrf2 activation and restoring redox homeostasis. In a murine model of retinal degeneration, a single intravitreal injection provided sustained preservation of retinal integrity for 28 days, significantly outperforming conventional peptide formulations and clinical supplements. This work offers a precise, mechanism-based solution for RPE-targeted regulation therapies and establishes a paradigm for designing peptide nanotherapeutics that circumvent the intrinsic limitations of retinal drug delivery.