Inflammation Education-Empowered Extracellular Vesicles Targeting Inflammation-Oxidative Stress Interplay for AKI Therapy

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.