Targeted no-releasing L-arginine-induced hesperetin self-assembled nanoparticles for ulcerative colitis intervention

Overproduction of reactive oxygen species (ROS) plays a crucial role in initiating and advancing ulcerative colitis (UC), and the persistent cycle between ROS and inflammation accelerates disease development. Therefore, developing strategies that can effectively scavenge ROS and provide targeted intervention are crucial for the management of UC. In this study, we synthesized natural carrier-free nanoparticles (HST-Arg NPs) using the Mannich reaction and π-π stacking for the intervention of UC. HST-Arg NPs are an oral formulation that exhibit good antioxidant capabilities and gastrointestinal stability. Benefiting from the negatively charged characteristics, HST-Arg NPs can specifically accumulate in positively charged inflamed regions of the colon. Furthermore, in the oxidative microenvironment of colonic inflammation, HST-Arg NPs respond to ROS by releasing nitric oxide (NO). In mice model of UC induced by dextran sulfate sodium (DSS), HST-Arg NPs significantly mitigated colonic injury by modulating oxidative stress, lowering pro-inflammatory cytokines, and repairing intestinal barrier integrity. In summary, this convenient and targeted oral nanoparticle can effectively scavenge ROS at the site of inflammation and achieve gas intervention, offering robust theoretical support for the development of subsequent oral formulations in related inflammatory interventions. STATEMENT OF SIGNIFICANCE: Nanotechnology has been extensively explored in the biomedical field, but the application of natural carrier-free nanotechnology in this area remains relatively rare. In this study, we developed a natural nanoparticle system based on hesperetin (HST), L-arginine (L-Arg), and vanillin (VA) to scavenge ROS and alleviate inflammation. In the context of ulcerative colitis (UC), the synthesized nanoparticles exhibited excellent intervention effects, effectively protecting the colon from damage. Consequently, these nanoparticles provide a promising and precise nutritional intervention strategy by addressing both oxidative stress and inflammatory pathways simultaneously, demonstrating significant potential for application.