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Dual-targeted molybdenum nanomedicine treats acute pancreatitis by blocking mitochondrial DNA-triggered cGAS-STING
Jinjin Liu1, Dan Wang2, Shuya Wang3
1Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China; Department of General Surgery, Division of Biliopancreatic Surgery and Bariatric Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
Abstract:
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.
Insights
A new nanomedicine, MTP, effectively treats acute pancreatitis by scavenging mitochondrial ROS and blocking inflammation. It targets damaged barriers and pancreatic cells, offering a breakthrough therapy.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Inflammation Research
Background:
- Acute pancreatitis involves mitochondrial reactive oxygen species (ROS) overproduction in pancreatic acinar cells (PACs), leading to cell damage and apoptosis.
- Released mitochondrial DNA (mt-DNA) activates the cGAS-STING pathway in macrophages, exacerbating inflammation and disease progression.
- Existing therapies struggle to reach damaged pancreatic mitochondria due to the blood-pancreas barrier (BPB).
Purpose of the Study:
- To develop a novel dual-targeting nanomedicine for acute pancreatitis (AP).
- To overcome the limitations of current treatments in penetrating the BPB and targeting mitochondria.
- To investigate the therapeutic efficacy of the nanomedicine in mitigating ROS-mediated PAC damage and macrophage-driven inflammation.
Main Methods:
- Synthesis of MTP, a dual-targeting nanomedicine from tannic acid, dopamine, and molybdenum oxides.
- Demonstration of MTP's active homing to injured BPB and specific accumulation within PAC mitochondria.
- Evaluation of MTP's ability to scavenge mitochondrial ROS, protect mitochondrial integrity, reduce mt-DNA release, and inhibit PAC apoptosis.
Main Results:
- MTP effectively scavenges mitochondrial ROS within PACs, preserving mitochondrial integrity and reducing mt-DNA leakage.
- MTP inhibits mt-DNA-induced cGAS-STING activation in macrophages, suppressing M1 polarization and inflammation.
- The dual-targeting strategy successfully mitigates AP progression by addressing both cellular damage and inflammatory responses.
Conclusions:
- MTP represents a breakthrough therapeutic approach for acute pancreatitis.
- Dual-targeting nanomedicine offers a promising strategy for overcoming BPB limitations and treating mitochondrial dysfunction.
- MTP effectively halts the cycle of ROS overproduction, mt-DNA release, and macrophage-driven inflammation in AP.
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