RNA interference (RNAi), a naturally occurring gene-silencing mechanism, has emerged as a promising platform for developing innovative, non-genetically modified (GM) plant protection products. In the context of climate change, biodiversity loss, and growing resistance to traditional pesticides, the need for highly specific, environmentally compatible alternatives for sustainable pest management is increasing. RNAi-based sprays are a novel approach in which double-stranded RNA (dsRNA) molecules silence essential genes in target pests without acting like toxic conventional compounds. A significant advancement in this technology occurred with the 2023 approval of Calantha™ (Ledprona) in the USA, marking the first authorization of an RNAi-based biopesticide for agricultural use. Ledprona targets the Colorado potato beetle by silencing specific genes following foliar dsRNA application. Here, we summarize the mechanism of action, efficacy, environmental behavior, and safety assessment of Ledprona as evaluated by the US Environmental Protection Agency. In addition, we discuss the broader regulatory implications of this approval and highlight key challenges and opportunities for assessing and implementing RNAi-based plant protection products within the European Union's regulatory framework. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.