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Integrated Cascade Nanozymes with Antisenescence Activities for Atherosclerosis Therapy
Wanling Liu1, Yihong Zhang1, Gen Wei1
1College of Engineering and Applied Sciences, Nanjing National Laboratory of Microstructures, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, 210023, Nanjing, Jiangsu, China.
Abstract:
Senescent cells are the critical drivers of atherosclerosis formation and maturation. Mitigating senescent cells holds promise for the treatment of atherosclerosis. In an atherosclerotic plaque microenvironment, senescent cells interact with reactive oxygen species (ROS), promoting the disease development. Here, we hypothesize that a cascade nanozyme with antisenescence and antioxidant activities can serve as an effective therapeutic for atherosclerosis. An integrated cascade nanozyme with superoxide dismutase- and glutathione peroxidase-like activities, named MSe1 , is developed in this work. The obtained cascade nanozyme can attenuate human umbilical vein endothelial cell (HUVEC) senescence by protecting DNA from damage. It significantly weakens inflammation in macrophages and HUVECs by eliminating overproduced intracellular ROS. Additionally, the MSe1 nanozyme effectively inhibits foam cell formation in macrophages and HUVECs by decreasing the internalization of oxidized low-density lipoprotein. After intravenous administration, the MSe1 nanozyme significantly inhibits the formation of atherosclerosis in apolipoprotein E-deficient (ApoE-/- ) mice by reducing oxidative stress and inflammation and then decreases the infiltration of inflammatory cells and senescent cells in atherosclerotic plaques. This study not only provides a cascade nanozyme but also suggests that the combination of antisenescence and antioxidative stress holds considerable promise for treating atherosclerosis.
Insights
This study introduces a novel nanozyme that combats atherosclerosis by targeting senescent cells and reducing oxidative stress. This dual-action approach effectively inhibits disease progression in mice, offering a promising new therapeutic strategy.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Nanotechnology
Background:
- Senescent cells are key drivers in atherosclerosis development and progression.
- The atherosclerotic plaque microenvironment involves interactions between senescent cells and reactive oxygen species (ROS), exacerbating the disease.
- Targeting senescent cells and oxidative stress presents a potential therapeutic avenue for atherosclerosis.
Purpose of the Study:
- To develop and evaluate a novel cascade nanozyme with combined antisenescence and antioxidant activities for atherosclerosis treatment.
- To investigate the efficacy of the nanozyme in mitigating cellular senescence, inflammation, and foam cell formation.
- To assess the therapeutic potential of the nanozyme in a mouse model of atherosclerosis.
Main Methods:
- Development of an integrated cascade nanozyme (MSe1) with superoxide dismutase and glutathione peroxidase-like activities.
- In vitro assessment of MSe1's effects on human umbilical vein endothelial cell (HUVEC) senescence, ROS elimination, and oxidized low-density lipoprotein (oxLDL) uptake in macrophages and HUVECs.
- In vivo evaluation of MSe1's therapeutic efficacy in apolipoprotein E-deficient (ApoE-/-) mice with atherosclerosis.
Main Results:
- The MSe1 nanozyme attenuated HUVEC senescence by protecting DNA and reduced intracellular ROS in macrophages and HUVECs, thereby weakening inflammation.
- MSe1 inhibited foam cell formation by decreasing oxLDL internalization.
- Intravenous administration of MSe1 significantly inhibited atherosclerosis formation in ApoE-/- mice, reducing oxidative stress, inflammation, and senescent cell infiltration in plaques.
Conclusions:
- A novel cascade nanozyme (MSe1) with dual antisenescence and antioxidant properties was successfully developed.
- The MSe1 nanozyme demonstrates significant therapeutic potential for atherosclerosis by targeting key pathological mechanisms.
- Combining antisenescence and antioxidative stress strategies offers a promising approach for the effective treatment of atherosclerosis.
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