<jats:title>Abstract</jats:title>
          <jats:sec>
            <jats:title>Background</jats:title>
            <jats:p>Acute pancreatitis (AP) is a severe inflammatory disease frequently accompanied by disturbances in glucose metabolism, which further complicate the disease prognosis. This study aims to explore the role of PFKFB3, a key glycolytic enzyme, in regulating glucose metabolism in AP and assess the potential of PFKFB3 inhibition via nanovesicle delivery to mitigate metabolic dysfunction.</jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Methods</jats:title>
            <jats:p>Transcriptomic data from Gene Expression Omnibus (GEO), including single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing, were analyzed to investigate the molecular mechanisms involved in glucose metabolism dysregulation in AP. The therapeutic effects of PFKFB3 inhibition via nanovesicle-based delivery were evaluated using both in vivo and in vitro AP models.</jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Results</jats:title>
            <jats:p>PFKFB3 inhibition significantly restored normal glycolytic function and improved glucose metabolism in AP models. Moreover, nanovesicle-mediated delivery also alleviated both inflammation and metabolic disturbances, highlighting its promise as a therapeutic strategy for managing glucose dysfunction in AP.</jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Conclusion</jats:title>
            <jats:p>Our findings identify PFKFB3 as a critical therapeutic target for treating glucose metabolism disorders in acute pancreatitis. Nanovesicle-based PFKFB3 inhibition may serve as an innovative approach to address metabolic complications associated with AP, offering a new direction for therapeutic interventions in inflammatory diseases.</jats:p>
          </jats:sec>
          <jats:sec>
            <jats:title>Graphical Abstract</jats:title>
            <jats:p>Molecular Mechanism of EVs-mediated Delivery of PFKFB3 Inhibitor in Ameliorating Glucose Metabolism Disorder Post-AP.</jats:p>
          </jats:sec>