Multifunctional Nanomedicine for Targeted Atherosclerosis Therapy: Activating Plaque Clearance Cascade and
Cui Tang1,2,3, Hui Wang3, Lina Guo1
1Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
Abstract:
Atherosclerosis (AS) is a prevalent inflammatory vascular disease characterized by plaque formation, primarily composed of foam cells laden with lipids. Despite lipid-lowering therapies, effective plaque clearance remains challenging due to the overexpression of the CD47 molecule on apoptotic foam cells, inhibiting macrophage-mediated cellular efferocytosis and plaque resolution. Moreover, AS lesions are often associated with severe inflammation and oxidative stress, exacerbating disease progression. Herein, we introduce a multifunctional nanomedicine (CEZP) targeting AS pathogenesis via a "cell efferocytosis-lipid degradation-cholesterol efflux" paradigm, with additional anti-inflammatory properties. CEZP comprises poly(lactic-co-glycolic acid) nanoparticles encapsulated within a metal-organic framework shell coordinated with zinc ions (Zn2+) and epigallocatechin gallate (EGCG), enabling CpG encapsulation. Upon intravenous administration, CEZP accumulates at AS plaque sites, facilitating macrophage uptake and orchestrating AS treatment through synergistic mechanisms. CpG enhances cellular efferocytosis, Zn2+ promotes intracellular lipid degradation, and EGCG upregulates adenosine 5'-triphosphate-binding cassette transporters for cholesterol efflux while also exhibiting antioxidant and anti-inflammatory effects. In vivo validation confirms CEZP's ability to stabilize plaques, reduce lipid burden, and modulate the macrophage phenotype. Moreover, CEZP is excreted from the body without safety concerns, offering a low-toxicity nonsurgical strategy for AS plaque eradication.
Insights
A novel nanomedicine, CEZP, enhances efferocytosis and lipid degradation to clear atherosclerotic plaques. This safe, low-toxicity treatment offers a promising nonsurgical strategy for atherosclerosis management.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Cardiovascular Research
Background:
- Atherosclerosis (AS) involves lipid-laden foam cells and inflammation, hindering plaque resolution.
- Overexpressed CD47 on apoptotic foam cells inhibits efferocytosis, impeding macrophage-mediated clearance.
- Existing therapies struggle with effective plaque clearance and managing inflammation/oxidative stress in AS.
Purpose of the Study:
- To develop a multifunctional nanomedicine (CEZP) for atherosclerosis treatment.
- To target AS pathogenesis through a synergistic "cell efferocytosis-lipid degradation-cholesterol efflux" paradigm.
- To evaluate CEZP's anti-inflammatory and antioxidant properties for enhanced AS plaque eradication.
Main Methods:
- CEZP nanoparticles composed of PLGA, MOF shell with Zn2+, EGCG, and CpG.
- Intravenous administration of CEZP for targeted accumulation at AS plaque sites.
- In vivo validation of CEZP's efficacy in plaque stabilization, lipid reduction, and macrophage modulation.
Main Results:
- CEZP administration enhanced cellular efferocytosis via CpG.
- Zinc ions (Zn2+) promoted intracellular lipid degradation.
- Epigallocatechin gallate (EGCG) facilitated cholesterol efflux and reduced inflammation/oxidative stress.
- In vivo studies demonstrated plaque stabilization, reduced lipid burden, and modulated macrophage phenotype.
- CEZP showed low toxicity and efficient excretion.
Conclusions:
- CEZP effectively targets atherosclerosis through a multi-pronged approach.
- The nanomedicine promotes efferocytosis, lipid degradation, and cholesterol efflux.
- CEZP offers a safe, low-toxicity, nonsurgical strategy for AS plaque eradication.
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