Melittin Nanoparticles Mitigate Glyphosate-Induced Nephrotoxicity via Cytokine Modulation and Bax/Nrf2 Pathways

<b>Background/Objectives:</b> Glyphosate-based herbicides (GBHs) are widely used agrochemicals implicated in nephrotoxicity through mechanisms involving oxidative stress, inflammation, and tissue remodeling. Natural peptides such as melittin possess potent anti-inflammatory and antioxidant properties; however, their therapeutic use is limited by instability and toxicity. Nanotechnology-based encapsulation presents a promising approach to overcoming these challenges. Objective: This study aimed to evaluate the protective effects of melittin-loaded chitosan-TPP nanoparticles (MEL-NPs) against glyphosate-induced nephrotoxicity in rats, with emphasis on oxidative, inflammatory, and apoptotic pathways. <b>Methods:</b> Female Wistar rats were divided into four groups: control, glyphosate (5 mg/kg/day, 25 days), glyphosate + free melittin, and glyphosate + MEL-NPs (40 µg/kg, orally, 3 times/week). Renal function biomarkers, oxidative stress parameters (MDA, GSH, SOD, CAT, NO), cytokines (TNF-α, IL-6), and serum protein/iron indices were assessed. Western blotting (Nrf2, NGAL), histopathology (H&E), and immunohistochemistry (Bax) were performed. Nanoparticles were characterized by TEM, FTIR, and UV-Vis spectroscopy. <b>Results:</b> Glyphosate exposure caused renal dysfunction, including elevated plasma urea and creatinine levels, and reduced creatinine clearance, indicating impaired glomerular filtration efficiency, oxidative stress (↑increased MDA, NO; ↓decreased GSH, SOD), and upregulation of pro-inflammatory cytokines. Histology revealed tubular degeneration and inflammatory infiltration, while NGAL and Bax were strongly induced. Nrf2 expression was elevated as a compensatory response. Free melittin partially ameliorated these alterations, whereas MEL-NPs provided superior protection, restoring renal function, normalizing oxidative balance, reducing NGAL and Bax expression, and preserving renal histoarchitecture. <b>Conclusions:</b> Melittin nanoparticles confer robust renoprotection against glyphosate-induced nephrotoxicity in rats by modulating oxidative stress, suppressing inflammation, and regulating Nrf2/Bax signaling. These findings highlight nano-melittin as a promising therapeutic platform for managing herbicide-related renal disorders.