Related Experiment Video
Updated: May 13, 2025
Synthesis of Monocyte-targeting Peptide Amphiphile Micelles for Imaging of Atherosclerosis
Published on: November 17, 2017
Dual-targeted microbubbles for atherosclerosis therapy: Inducing M1 macrophage apoptosis by inhibiting telomerase
Wei Zeng1, Zhengan Huang2, Yalan Huang1,3
1Shenzhen Medical Ultrasound Engineering Center, Department of Ultrasonography, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China.
Abstract:
The progression of atherosclerosis (AS) is closely associated with M1 macrophages. Although the activation of macrophage telomerase during plaque formation has been documented, targeted modulation strategies remain challenging. In this study, we developed a dual-target microbubble-delivery system (Ab-MMB1532) encapsulating BIBR1532, a telomerase inhibitor, for the targeted therapy of AS. This system exhibited remarkable targeting capabilities towards M1 macrophages, with its targeting advantage notably accentuated under high shear forces. Mechanistically, Ab-MMB1532 inhibited telomerase activity by downregulating telomerase reverse transcriptase (TERT) expression, subsequently inducing caspase-3-mediated apoptosis. Integrated multi-omics profiling revealed that the inhibition of the NF-κB pathway served as the central regulatory hub. In vivo studies further confirmed that Ab-MMB1532 effectively targets and accumulates within AS lesions, promoting M1 macrophage apoptosis through the inhibition of the TERT/NF-κB signaling axis, and significantly reducing plaque burden (25.4 % reduction vs. controls, p < 0.001). In summary, our findings suggest a novel approach for telomerase-targeted therapy in AS.
Insights
A novel microbubble system targets M1 macrophages in atherosclerosis (AS) by inhibiting telomerase. This approach reduces plaque burden by inducing apoptosis and inhibiting the TERT/NF-κB pathway.
Area of Science:
- Cardiovascular Research
- Macrophage Biology
- Molecular Therapy
Background:
- Atherosclerosis (AS) progression is linked to M1 macrophages.
- Targeting macrophage telomerase in AS plaque formation is challenging.
Purpose of the Study:
- To develop a dual-target microbubble system (Ab-MMB1532) for targeted therapy of AS.
- To investigate the mechanism of Ab-MMB1532 in inhibiting M1 macrophages and AS progression.
Main Methods:
- Development of Ab-MMB1532 encapsulating the telomerase inhibitor BIBR1532.
- Assessment of targeting capabilities towards M1 macrophages under varying shear forces.
- Multi-omics profiling to elucidate the regulatory pathways involved.
- In vivo studies in AS models to evaluate therapeutic efficacy.
Main Results:
- Ab-MMB1532 demonstrated enhanced targeting of M1 macrophages, particularly under high shear forces.
- Inhibition of telomerase activity via downregulation of telomerase reverse transcriptase (TERT) expression.
- Induction of caspase-3-mediated apoptosis in M1 macrophages.
- Identification of NF-κB pathway inhibition as a central regulatory mechanism.
- In vivo studies showed effective accumulation in AS lesions, M1 macrophage apoptosis, and significant plaque burden reduction (25.4%).
Conclusions:
- Ab-MMB1532 offers a novel strategy for telomerase-targeted therapy in atherosclerosis.
- The TERT/NF-κB signaling axis is a key target for AS treatment.
- This approach effectively reduces AS plaque burden by modulating M1 macrophage activity.
