ROS-Responsive Melanin-Like Nanomaterials And Their Therapeutic Application In Inflammatory Bowel Disease

Inflammatory bowel disease（IBD）is a chronic non-specific inflammatory bowel disease.Since the etiology of IBD is unknown,it cannot be cured till now.Recently,the incidence of IBD has been increasing annually,making it one of the key issues of concern in the global biomedical field.It has been revealed that chronic inflammation and reactive oxygen species（ROS）imbalance can exacerbate the disease by inducing oxidative stress.Therefore,regulating the oxidative-reductive balance in the lesion site has become a new approach to IBD treatment.This study aims to address the limitations of ordinary nanoantioxidants,such as biosecurity risks,low compliance of administration,unstability in gastrointestinal tract with complex chemical and physiological environment,and low retention in colorectum.The study focused on designing a ROS-responsive nanoantioxidant derived from melanin,which possess antioxidant activity.The nanoantioxidants was designed as an oral preparation by combining inulin,which has intestinal hydrolysis and retention characteristics.The antioxidaive performance and the efficacy of IBD both in vitro and in vivo model were evaluated.（1）The ROS-responsive melanin precursor,p PLD,was synthesized using levodopa as the skeleton.Phenylboronic acid group,a ROS-sensitive group,was modified on levodopa.The chemical structure of the p PLD was confirmed using nuclear magnetic resonance and infrared spectroscopy.In a H₂O₂ solution（100 m M）,p PLD could respond to ROS and self-oxidize into melanin-like nanoparticles by exposing its dopamine structure,showing ROS-responsive activity.（2）The p PLD nanoparticles（p PLDN）was prepared via a precipitation method,followed by encapsulation with quaternized inulin（QI）to obtain a double-layered oral preparations,p PLDN/QI-1 and p PLDN/QI-2.The morphological test results showed that the average particle size of the oral preparations was approximately 220 nm.The nanoparticles showed regular shape and uniform distribution.Both p PLDN and the two p PLDN/QI samples exhibited broad-spectrum antioxidant activity and could effective ROS-scavenging activity.（3）RAW264.7 and Caco-2 cells were used to establish an inflammation cell model using H₂O₂.After treatment,all groups of p PLDN,p PLDN/QI-1,and p PLDN/QI-2 could reduce the of lipid peroxidation level and alleviate the damage by clearing intracellular ROS,showing comparable antioxidant activity of melanin-like nanoparticles（p PDAN）.（4）In vivo IBD model was induced by dextran sodium sulfate（DSS）.After oral administration,the treated groups showed significant relief of IBD symptoms in mice.The pathological damage was restored,indicating better efficacy than that of 5-aminosalicylic acid.In summary,this study developed a novel oral ROS-responsive nanomaterial with excellent biocompatibility and antioxidant activity.The results showed the nanomaterial could show excellent efficacy in both in vitro and in vivo IBD models.Combingning with its good biocompatibility,these ROS-responsive nanomaterials are promising in the application of IBD therapy.