Intestinal stem cells (ISCs) engage in proliferation to maintain a stable stem cell population and differentiate into functional epithelial subpopulations. This intricate process is upheld by various signals derived from the host and gut microbiota, establishing an ISC niche. However, during inflammatory bowel disease (IBD), this signaling niche undergoes dramatic changes, leading to impaired ISC and hindered restoration of the damaged intestinal epithelial barrier. This study introduces intestinal inflammatory microenvironment-responsive microsphere vehicles designed to remodel the ISC niche, offering an approach to treat IBD. Using an advanced emulsion technique, these microsphere vehicles specifically target colonic inflammation sites, delivering a responsive release of MXene and l-arginine. This delivery system is formulated to modulate intestinal flora and immune responses effectively. l-arginine is converted into nitric oxide to regulate the gut microbiome, while MXene serves as a nanoimmunomodulator to stabilize immune homeostasis. Our findings demonstrate that the anti-inflammatory properties of the microspheres are key to promoting epithelial repair and remodeling of the ISC niche. This study highlights the role of antioxidant microspheres as anti-inflammatory agents that indirectly support ISC function and gut regeneration.