Novel mRNA Therapy for Acute Pancreatitis

Acute pancreatitis (AP) is associated with high mortality and is characterized by increased acinar cell death and premature release and activation of digestive enzymes. During the acute phase, AP is accompanied by enhanced efferocytosis to clear apoptotic cells. The Anxa1 protein is crucial for efferocytosis, but its role in AP remains unclear. Recently, researchers published a study titled "Annexin A1 mRNA-loaded liposomes alleviate acute pancreatitis by suppressing the STING pathway and promoting efferocytosis in macrophages" in Nature Nanotechnology.

This study developed a novel mRNA therapy for alleviating acute pancreatitis. Using nanoliposomes to deliver Anxa1 mRNA, the study alleviated acute pancreatitis by inhibiting the STING pathway and promoting macrophage efferocytosis.

Acute pancreatitis (AP) is characterized by necrotic cell death of acinar cells, leading to pancreatic necrosis and the release of molecular patterns associated with nuclear damage, proinflammatory mediators, and inflammatory chemokines. During the acute phase of AP, macrophages rapidly clear phagocytosed apoptotic cells, a process known as efferocytosis, to prevent an inappropriate inflammatory response. Efferocytosis is a highly conserved process triggered by multiple phagocytic ligands, including the Anxa1 protein. Anxa1 binds to phosphatidylserine on the surface of apoptotic cells in a calcium-dependent manner and promotes phagocytosis of apoptotic cells by macrophages. Recent studies have implicated activation of the STING signaling pathway in the pathogenesis of AP.

In the past few years, mRNA-based therapies have emerged as a promising therapeutic strategy. However, poor mRNA stability has limited its clinical application. To address this issue, researchers have used nanocarriers for mRNA delivery to enhance its stability and targeting capabilities. Nanoliposomes have been used as delivery vehicles for both siRNA and mRNA. However, the clinical application of nanoliposome-based mRNA delivery systems remains limited, in part due to their clearance by the immune system during circulation.

Figure 1. Myeloid Anxa1 deficiency-dependent induction of type I IFN mediated by cGAS-STING pathway. (Fang H, et al., 2025)

In this latest study, the research team demonstrated that deficiency of the Anxa1 protein abolishes pancreatic macrophage efferocytosis, leading to the accumulation and necrosis of apoptotic acinar cells. Building on this finding, the team further demonstrated that nanoliposomes loaded with Anxa1 mRNA can restore macrophage efferocytosis by inhibiting the cGAMP-cGAS-STING pathway, thereby alleviating the pathology of acute pancreatitis (AP).

Collectively, this study reveals a critical function of Anxa1 in macrophage efferocytosis during acute pancreatitis and demonstrates a novel nanotechnology approach for the treatment of acute pancreatitis, which may have potential therapeutic value in humans.

Reference

Fang H, et al. Annexin A1 mRNA-loaded liposomes alleviate acute pancreatitis by suppressing STING pathway and promoting efferocytosis in macrophages. Nature Nanotechnology, 2025: 1-12.