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Sepsis-associated intestinal injury represents a critical pathological event contributing to multiple organ dysfunction, with its pathogenesis closely linked to excessive oxidative stress and hyperactivated endoplasmic reticulum stress. Current clinical interventions lack the capacity for precise modulation of the intestinal microenvironment, while existing nanozyme systems generally face challenges such as low oral delivery efficiency, insufficient stability, and uncertain biosafety. To address these limitations, we developed a novel oral nanozyme delivery system based on 2D V₂C MXene. Through surface modification with hydroxyethyl cellulose (HEC), we constructed a V₂C@HEC (CV) nanozyme with enhanced physiological stability and intestinal mucoadhesion. In both in vitro and in vivo studies, the CV nanozyme demonstrated significant reactive oxygen species (ROS)-scavenging capacity. Oral administration of CV effectively mitigated intestinal barrier damage and improved survival in a septic mouse model. Mechanistic investigations suggested that the protective effects of CV may be associated with ROS clearance and modulation of endoplasmic reticulum stress, with inhibition of the ATF6/CHOP signaling pathway potentially serving as one underlying mechanism for its cytoprotective function. In summary, this study not only presents a novel nanozyme material with favorable biocompatibility, excellent stability, and a defined antioxidant mechanism, but also provides an innovative materials-based strategy for the treatment of sepsis.