<p>Acute pancreatitis (AP) is associated with a high mortality rate, and thereby its therapy is still a challenge. At the molecular level, single-cell RNA sequencing (scRNA-seq) analysis revealed a marked upregulation of pyroptosis (a recently characterized inflammatory programmed cell death pathway) and its key molecular complexes during AP, highlighting the pivotal role of pyroptosis in AP progression. Concurrently, the excessive activation of digestive enzymes within acinar cells triggers pancreatic tissue autodigestion, which exerts profoundly deleterious effects. Thus, in response to these AP pathological characteristics, this study designed a multi-enzyme catalytic system to attenuate pancreatic acinar cell pyroptosis, inactivate pancreatic enzymes, and suppress excessive inflammatory infiltration in pancreatic tissue. Herein, single-atom nanozymes of Co-based SAE (Co-SAE) with inherent antioxidant enzymes surface modified with trypsin activity inhibitor Rhamnetin (Rh) were developed to recover from AP and inhibit the progression of severe acute pancreatitis (SAP). It is found that this formulation (Rh@SAE) conferred effective protection against self-digestion, oxidative stress, inflammatory cell infiltration, tissue damage. Importantly, pyroptotic death of pancreatic acinar cells (PACs) is alleviated as validated by the blockade of GSDMD cleavage, inactivation of caspase 1, and reduction in the release of inflammatory cytokines (IL-1β) and lactate dehydrogenase (LDH). Overall, this work holds significant potential for improving AP outcomes, which opens a new avenue for catalytic therapy in AP.</p> Graphical Abstract <p></p>