Virus-biomimetic melanin nanoparticles with spiky structures and neutral zwitterionic shell for non-invasive prevention of dry AMD.

Clinically, no effective preventive strategies currently exist to inhibit the progression of early dry age-related macular degeneration (dAMD). Moreover, current retinal therapies rely on intravitreal injections, which carry inherent procedural risks. Inspired by natural melanin and viral structures, we developed virus-biomimetic melanin nanoparticles (VMNPs) surface-modified with ergothioneine (ET), featuring virus-like spike structures and a neutral zwitterionic shell. This study aimed to evaluate whether virus-inspired engineered nanoparticles could enhance retinal delivery and improve the therapeutic potential of melanin-based nanodrugs for dAMD. The VMNPs facilitated cellular uptake through both their virus-mimetic architecture and OCTN1-mediated active transport. They also exhibited potent antioxidant activity, significantly reducing intracellular and mitochondrial reactive oxygen species (ROS) in oxidative stress models of ARPE-19 cells. Transcriptomic analyses revealed that VMNPs activated intrinsic cytoprotective pathways by upregulating HMOX1and SLC7A11, while downregulating inflammation-associated genes. Importantly, VMNPs promoted transcytosis and, following topical administration, demonstrated improved retention and deep penetration within the rabbit eye, effectively reaching the retinal pigment epithelium (RPE) and deeper retinal layers. Notably, twice-daily topical administration of VMNPs markedly inhibited retinal degeneration in rabbits, achieving therapeutic efficacy comparable to a single intravitreal injection of pegcetacoplan. Collectively, these findings establish a promising paradigm for the non-invasive clinical treatment of dAMD.