• Human photoreceptors derived from retinal organoids do not transfer cytoplasmic material to mouse photoreceptors in vivo, regardless of donor age or recipient background.
• In vitro, human photoreceptors transfer fluorescent protein among themselves, but not with mouse photoreceptors, indicating species specificity of material transfer.
• A rare subset (<5%) of transplanted human photoreceptors can integrate into the mouse photoreceptor layer, but integration is not the primary mechanism of rescue.
• These findings suggest that xenograft models are unsuitable for studying human photoreceptor material transfer, but human photoreceptors remain competent donors for potential therapeutic cargo delivery.