Redox-Associated Suppression of Cytochrome P450 Detoxification by ZIF-8 Enables Sustainable Resistance Management in Brown Planthopper

Abstract The widespread evolution of insecticide resistance in agricultural pests threatens global food security and challenges the sustainability of crop protection. In Nilaparvata lugens, resistance to neonicotinoids is primarily driven by cytochrome P450-mediated metabolic detoxification, which substantially reduces insecticide efficacy. Herein, we developed a ZIF-8-based nanoformulation (CLO@ZIF-8) to improve clothianidin performance against resistant N. lugens. CLO@ZIF-8 exhibited uniform morphology, high loading capacity, and pH-responsive release behavior, that may facilitate insecticide availability under relevant physiological conditions. Bioassays demonstrated that CLO@ZIF-8 significantly enhanced insecticidal activity against resistant N. lugens under laboratory, pot, and field conditions. Notably, transcriptomic and qRT-PCR analyses revealed that ZIF-8 treatment significantly downregulated multiple cytochrome P450 genes, including the key resistance-associated gene CYP6ER1. Mechanistic analyses further showed that ZIF-8 treatment reduced intracellular ROS levels and suppressed multiple P450 genes involved in metabolic detoxification, particularly CYP6ER1. These responses were associated with enhanced clothianidin susceptibility in resistant N. lugens. Importantly, this regulatory effect was dependent on the integrated ZIF-8 nanostructure rather than its individual components. In addition, CLO@ZIF-8 showed favorable safety profiles toward rice and silkworms under the tested conditions. This work demonstrates the potential of integrating nano-enabled pesticide delivery with modulation of resistance-associated biological responses, providing a potential strategy for more sustainable insecticide resistance management.