Melanin nanoparticles-loaded lactobacillus fermentum exosomes for targeted and visualized treatment of ulcerative colitis.

Abstract

INTRODUCTION: Ulcerative colitis (UC) is chronic specific intestinal inflammation characterized by excessive reactive oxygen species, augmented inflammation, imbalanced microbiota and aberrant immune environment. However, conventional therapies are greatly limited due to the serious side effects and other technique problems. Multi-functional medicine should be designed and constructed to treat UC based on complex pathological mechanisms. OBJECTIVES: Antioxidant and microbiota regulator would be synergistically combined for the effective therapy of UC. MNPs-Lf-EVs, composed of melanin nanoparticles and Lactobacillus fermentum exosomes, would be developed for the treatment of UC through antioxidant and microbiota modulating effect. METHODS: MNPs-Lf-EVs were constructed through ultrasonication crushing method. The ability of scavenging free radicals, reducing apoptosis, inhibiting inflammation and promoting cell migration was examined on intestinal epithelium and macrophage. The targeting distribution was tracked by fluorescence and photoacoustic imaging. The efficacy and underlying mechanisms were conducted on colitis mice through HE staining, protein expression level and 16S rRNA sequencing analysis. RESULTS: Lf-EVs were extracted from Lactobacillus fermentum and melanin nanoparticles (MNPs) were synthesized and loaded into EVs to successfully prepare MNPs-Lf-EVs to attenuate UC. In vitro assays exerted the superior ability of MNPs-Lf-EVs to scavenge free radicals, reduce apoptosis, and regulate the expression of inflammatory cytokines. Both photoacoustic and fluorescence imaging results confirmed that MNPs-Lf-EVs could resist the harsh gastrointestinal environment to reach the inflammation colonic lesion and achieve colon-targeted visualized accumulation after oral administration. In vivo experiments demonstrated that MNPs-Lf-EVs effectively alleviated major symptoms, mitigated oxidative stress and inflammatory condition, and promoted the restoration of intestinal barrier. In addition, 16S rRNA sequencing data proved that MNPs-Lf-EVs could increase the diversity and species richness of intestinal microbiota. CONCLUSION: Natural origin property and green fabrication process of MNPs-Lf-EVs in this study may provide a safer and efficacious therapeutic platform for the targeted and visualization treatment of UC.