Electrically Driven Chimeric Extracellular Vesicles Crossing the Fundus Barrier for Retinoblastoma Treatment

The internal limiting membrane (ILM), which separates the vitreous from the retina, hinders the delivery of extracellular vesicles (EVs) to the fundus via intravitreal injection for retinoblastoma treatment. In addition, EVs need to traverse biological barriers and selectively target retinoblastoma cells. To address these challenges, we designed an electroactive microneedle (e-MN) device to actively propel macrophage- and retinoblastoma-derived chimeric EVs across the ILM and precisely localize them to tumor cells. This strategy significantly improved the concentration of EVs delivered to the retina in porcine, mouse, and rabbit eyes, 10-fold compared to conventional intravitreal injection at 6 h postadministration. Moreover, the chimeric EV system demonstrated superior retinoblastoma cell targeting, achieving a 2-fold increase in Y79 cell uptake compared with nonchimeric EVs, due to macrophage-mediated immune evasion and tumor-derived homologous recognition. The optogenetic system encapsulated in chimeric EVs induced apoptosis in ∼70% of tumor cells in vitro. Moreover, chimeric EVs delivered via e-MNs showed the highest ocular retention and visual function preservation among all of the tested approaches. This minimally invasive platform demonstrates a great potential for posterior segment drug delivery.