RNA interference is a promising crop protection technology that has seen rapid development in the past several years. Here, we investigated polyamino acid biopolymers, inorganic nanomaterials, and hybrid organic–inorganic nanomaterials for delivery of dsRNA and efficacy of gene knockdown using the model nematode Caenorhabditis elegans. Using an oral route of delivery, we are able to approximate how nanomaterials will be delivered in the environment. Of the materials investigated, only Mg–Al layered double-hydroxide nanoparticles were effective at gene knockdown in C. elegans, reducing marker gene expression to 66.8% of that of the control at the lowest tested concentration. In addition, we identified previously unreported injuries to the mouthparts of C. elegans associated with the use of a common cell-penetrating peptide, poly-l-arginine. Our results will allow the pursuit of further research into promising materials for dsRNA delivery and also allow for the exclusion of those with little efficacy or deleterious effects.