Dual-targeted molybdenum nanomedicine treats acute pancreatitis by blocking mitochondrial DNA-triggered cGAS-STING signaling via ROS modulation

Acute pancreatitis (AP), a potentially fatal disorder driven by macrophage-associated inflammation, involves mitochondrial reactive oxygen species (ROS) overproduction with pancreatic acinar cells (PACs). This ROS surge damages mitochondria, causing mitochondrial DNA (mt-DNA) leakage and PACs apoptosis. Released mt-DNA then activates the pro-inflammatory cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in macrophages, exacerbating disease progression. Critically, while scavenging mitochondrial ROS can halt this cycle, existing mitochondria-targeted drugs fail to penetrate the damaged blood-pancreas barrier (BPB). To overcome this limitation, we developed MTP, a novel dual-targeting nanomedicine synthesized from tannic acid, dopamine, and molybdenum oxides. MTP uniquely achieves dual targeting: actively homing to injured BPB and specifically accumulating within PACs mitochondria. This enables robust mitochondrial ROS scavenging, which protects mitochondrial integrity, reduces mt-DNA release, inhibits PACs apoptosis, and crucially blocks mt-DNA-induced cGAS-STING activation in macrophages, thereby suppressing their pro-inflammatory M1 polarization. By simultaneously interrupting both ROS-mediated PACs damage and macrophage-driven inflammation via this dual-targeting strategy, MTP effectively mitigates AP progression, establishing a breakthrough therapeutic approach.