Tetrahedron DNA Nanostructures as microRNA Inhibitors to Alleviate Acute Pancreatitis

Acute pancreatitis (AP) is an inflammatory pancreatic disorder characterized by tissue damage and necrosis. It not only affects the pancreas but also triggers systemic inflammatory responses, leading to multiorgan failure and potentially death. In recent years, microRNA (miRNA) sponges have demonstrated promise to enhance AP treatment outcomes by inhibiting specific miRNAs. However, the clinical implementation of these inhibitors is often compromised by their structural instability. In this study, we developed a tetrahedron DNA nanostructure (TDN) with a single-stranded DNA segment designed to capture miR-21-3p, a potential therapeutic target for AP, forming a robust miRNA inhibitor. The TDNs exhibited enhanced stability compared to conventional single-stranded miRNA inhibitors, allowing for efficient delivery in vivo and maximizing therapeutic efficacy. Following treatment with the TDN miRNA inhibitor, we observed significant changes in serum levels of biomarkers associated with pancreatitis. Notably, there was a decrease in the expression of specific cytokines associated with both local and systemic inflammatory responses, alongside changes in proteins related to cell death and apoptosis. The mechanism of action involves RNase H-mediated cleavage, which facilitates the inhibition of the target miRNA. Overall, our findings suggest that the TDN miRNA inhibitor can mitigate acute pancreatitis and subsequent multiorgan damage in mice, presenting an effective approach for the future management of AP.