Waterborne polyurethane nanoparticles incorporating linoleic acid as a potential strategy for controlling antibiotic resistance spread in the mammalian intestine

Plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) within the human and animal intestine represents a substantial global health concern. linoleic acid (LA) has shown promise in inhibiting conjugation <i>in vitro</i>, but its <i>in vivo</i> effectiveness in the mammalian intestinal tract is constrained by challenges in efficiently reaching the target site. Recent advancements have led to the development of waterborne polyurethane nanoparticles for improved drug delivery. In this study, we synthesized four waterborne polyurethane nanoparticles incorporating LA (WPU@LA) using primary raw materials, including N-methyldiethanolamine, 2,2'-(piperazine-1,4-diyl) diethanol, isophorone diisocyanate, castor oil, and acetic acid. These nanoparticles, identified as WPU_0.89@LA, WPU_0.99@LA, WPU_1.09@LA, and WPU_1.19@LA, underwent assessment for their pH-responsive release property and biocompatibility. Among these, WPU_0.99@LA displayed superior pH-responsive release properties and biocompatibility towards Caco-2 and IPEC-J2 cells. In a mouse model, a dosage of 10 mg/kg/day WPU_0.99@LA effectively reduced the conjugation of IncX4 plasmids carrying the mobile colistin resistance gene (<i>mcr-1</i>) by more than 45.1-fold. <i>In vivo</i> toxicity assessment demonstrated that 10 mg/kg/day WPU_0.99@LA maintains desirable biosafety and effectively preserves gut microbiota homeostasis. In conclusion, our study provides crucial proof-of-concept support, demonstrating that WPU_0.99@LA holds significant potential in controlling the spread of antibiotic resistance within the mammalian intestine.