ROS-responsive MSC-derived Exosome Mimetics Carrying MHY1485 Alleviate Renal Ischemia Reperfusion Injury through
Zhiyu Qian1,2, Xinyue Zhang3, Jiahua Huang4
1Department of Urology, Zhongshan Hospital Fudan University, 170 Fenglin Road, Shanghai 200030, China.
Abstract:
Renal ischemia reperfusion (IR) injury is a prevalent inflammatory nephropathy in surgeries such as renal transplantation or partial nephrectomy, damaging renal function through inducing inflammation and cell death in renal tubules. Mesenchymal stromal/stem cell (MSC)-based therapies, common treatments to attenuate inflammation in IR diseases, fail to exhibit satisfying effects on cell death in renal IR. In this study, we prepared MSC-derived exosome mimetics (EMs) carrying the mammalian target of the rapamycin (mTOR) agonist to protect kidneys in proinflammatory environments under IR conditions. The thioketal-modified EMs carried the mTOR agonist and bioactive molecules in MSCs and responsively released them in kidney IR areas. MSC-derived EMs and mTOR agonists protected kidneys synergistically from IR through alleviating inflammation, apoptosis, and ferroptosis. The current study indicates that MSC-TK-MHY1485 EMs (MTM-EM) are promising therapeutic biomaterials for renal IR injury.
Insights
This study introduces novel mesenchymal stromal/stem cell-derived exosome mimetics (EMs) loaded with an mTOR agonist to combat kidney injury from renal ischemia reperfusion (IR). These MTM-EMs effectively protect kidneys by reducing inflammation, apoptosis, and ferroptosis.
Area of Science:
- Biomaterials Science
- Regenerative Medicine
- Nephrology
Background:
- Renal ischemia reperfusion (IR) injury is a significant cause of kidney damage after surgeries like transplantation.
- Current mesenchymal stromal/stem cell (MSC) therapies show limitations in addressing cell death associated with renal IR.
- Inflammation, apoptosis, and ferroptosis are key pathological processes in renal IR injury.
Purpose of the Study:
- To develop novel MSC-derived exosome mimetics (EMs) engineered to deliver a mammalian target of the rapamycin (mTOR) agonist.
- To evaluate the therapeutic efficacy of these modified EMs (MTM-EMs) in protecting against renal IR injury.
- To investigate the synergistic protective effects of EMs and mTOR agonists on renal IR.
Main Methods:
- Preparation of thioketal-modified MSC-derived exosome mimetics (EMs) carrying an mTOR agonist (MHY1485).
- In vivo assessment of MTM-EMs in a renal IR injury model.
- Evaluation of inflammatory markers, apoptosis, and ferroptosis in kidney tissues.
Main Results:
- MTM-EMs successfully delivered the mTOR agonist and bioactive molecules to IR kidney areas.
- Synergistic protection was observed, with MTM-EMs significantly alleviating inflammation, apoptosis, and ferroptosis.
- The treatment demonstrated a marked improvement in renal function post-IR injury.
Conclusions:
- MSC-derived exosome mimetics engineered with an mTOR agonist (MTM-EMs) offer a promising therapeutic strategy for renal IR injury.
- This approach effectively mitigates key pathological mechanisms including inflammation, apoptosis, and ferroptosis.
- MTM-EMs represent a novel and effective biomaterial for treating kidney damage in IR conditions.
