A melatonin-based supramolecular nanosafener alleviates S-metolachlor-induced injury in maize

Maize, a global staple crop, faces severe yield and quality losses due to weed competition. While the herbicide S-metolachlor (S-MET) offers effective weed control, it induces phytotoxicity in maize. Although the safener benoxacor (BEN) alleviates herbicide damage, this safener, however, carries ecological toxicity risks. Natural safener melatonin (MT) is safer but limited by poor solubility, necessitating nano-enabled strategies to enhance its efficacy. In this study, a liposome-based nano-safener (MT@LIPs) was successfully developed through the hydrophobic interaction-driven encapsulation of MT into a vesicular structure self-assembled from cholesterol and phospholipids. It exhibited a small particle size and high solubility, significantly enhancing its soil migration ability and bioavailability. MT@LIPs significantly enhanced safening efficacy compared to free MT, increasing root length, fresh weight, plant height, and germination rate by 48.4%, 48.0%, 46.6%, and 36.6%, respectively, and even outperforming the commercial safener BEN. Mechanistic studies revealed that MT@LIPs can more effectively activate the glutathione metabolic pathway and starch and sucrose metabolism, while restoring the levels of key antioxidant functional-related genes (GST, GOR, SOD, and IDH1) and enzymes (glutathione S-transferase, superoxide dismutase, peroxidase, polyphenol oxidase, and catalase). Furthermore, MT@LIPs promoted the recovery of physiological and biochemical parameters, such as protein, amino acid, and chlorophyll, leading to enhanced safening effects. Importantly, the nano-formulation showed excellent biosafety across various biological models, including zebrafish (Danio rerio) embryos, human skin fibroblasts, and fruit flies (Drosophila melanogaster). This work not only reports an innovative nano-enabled safener but also offers a feasible strategy to bridge the gap between theoretical development and practical application of natural safeners.