Natural small RNA-based defense informs engineering of host-induced gene silencing in plant disease resistance

Host-induced gene silencing (HIGS) is a crop protection strategy that exploits RNA interference (RNAi) to silence targeted genes in invading pathogens or pests and reduce disease. Despite some successful examples of HIGS in laboratory settings, its translation into commercial agriculture has been limited. Recent discoveries demonstrating that plants deploy specific endogenous small RNAs (sRNAs) to regulate gene expression in fungi and oomycetes have broadened our understanding of natural trans-species RNAi (natural-tsRNAi) and provided a framework for improving applications of sRNA-based defense. In this review, we summarize HIGS studies published between 2021 and 2025 with a meta-analysis, highlighting their potential and limitations. We then discuss recent advances in natural tsRNAi with an emphasis on the secondary small interfering RNA pathway as a native immune response. Finally, we provide our opinion on how insights from natural tsRNAi inform design principles for sRNA-based immunity as a promising source of engineering durable resistance traits.