Nanoplastics (NPs) are emerging contaminants that have received worldwide attention due to their threats to human health. Although NPs have been reported to cause adverse effects on animal retinas, their potential effects on the human retina are poorly understood. This study aims to investigate the impact of polystyrene-NPs (PS-NPs) on human neural retina organoids (hNROs), which mimic the early developing neural retina. hNROs were generated and exposed to PS-NPs with diameters of 100, 200, and 500 nm at concentrations of 0.04, 0.1, and 0.25 mg/mL for two weeks. Smaller-sized PS-NPs induced more severe neurotoxicity to hNROs, as evidenced by decreased organoid size, reduced cell proliferation, increased apoptosis, and altered gene expression profiles. All sizes of PS-NPs exerted toxic effects on retinal development by disrupting axon guidance, anatomical structure development, differentiation, and neurogenesis. PS-NPs exhibited concentration-dependent neurotoxicity, with increasing severity at higher concentrations. Compared with early-stage exposure, pre-early-stage exposure to PS-NPs resulted in a more pronounced inhibition in organoid growth and development. Moreover, we investigated the combined neurotoxic effects of PS-NPs and cadmium (one of the most common heavy metals) exposure. Co-exposure was found to enhance the retinal toxicity of PS-NPs. Collectively, this study demonstrates that NP-induced retinal toxicity exhibits size-, dose-, and developmental stage-dependent effects, advancing our understanding of their health risks.
