Abstract: TH-PO034
Inflammation Education-Empowered Extracellular Vesicles Targeting Inflammation-Oxidative Stress Interplay for AKI Therapy
Session Information
- AKI: Epidemiology, Risk Factors, and Prevention - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 101 AKI: Epidemiology, Risk Factors, and Prevention
Author
- Zhang, Chuyue, Sichuan University, Chengdu, Sichuan, China
Group or Team Name
- Dept of Nephrology and Institute of Kidney Diseases, West China Hospital, Sichuan University.
Background
Acute kidney injury (AKI) lacks effective pharmacological interventions, and the mutually exacerbating inflammation and oxidative stress are major pathophysiological mechanisms.
Methods
Inspired by mesenchymal stem cells' (MSCs) capability to respond to inflammatory environment, we educated them to generate primed extracellular vesicles (pEVs) endowed with anti-inflammatory properties. Further we engineered these pEVs by conjugating them with a mitochondria-targeted antioxidant SS31 using a reactive oxidative species (ROS)-responsive linker, resulting in the creation of pEV-TK-SS31.
Results
This pEV-TK-SS31 achieved kidney-targeting through the upregulation of integrin α4β1 acquired from the education process, which facilitated binding to inflammatory ligand VCAM-1 at injured sites. By analyzing renal function, pathological damage, oxidative stress and inflammation, pEV-TK-SS31 demonstrated superior therapeutic efficacy in both ischemia/reperfusion and sepsis-induced AKI models. Mechanistically, pEVs, carrying increased anti-inflammatory miRNAs due to education process, mitigated inflammation via suppressing IRAK1/TRAF6 signaling, and alleviated oxidative stress by site-specifically releasing SS31 upon ROS-induced cleavage.
Conclusion
This smart system, which could be employed for other combination therapies of customized anti-inflammatory cargo and therapeutic agents, holds promise for AKI treatment and inflammation/oxidative stress-related disorders.
Funding
- Government Support – Non-U.S.