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Dual-Targeted Microbubbles Promote Apoptosis of M1 Macrophages by Inhibiting Telomerase Activity for Atherosclerosis Therapy

Liu, Y.; Zeng, W.; Huang, Z.; Huang, Y.; Xiong, K.; Sheng, Y.; Lin, X.; Zhong, X.; Ye, J.; Guo, Y.; Arkin, G.; Xu, J.; Fei, H.

2024-08-07 bioengineering
10.1101/2024.08.01.606265 bioRxiv
Show abstract

It is known that M1 macrophages are the dominant phenotype in progressive atherosclerosis (AS). Studies have shown that telomerase in macrophages can be activated during the atherosclerosis formation, but how to regulate the telomerase activity of M1 macrophages is the focus of treatment of AS. Herein, we report a dual-targeted microbubbles delivery system encapsulating the telomerase inhibitor BIBR1532 (Ab-MMB1532), designed for precise targeted therapy of AS. The Ab-MMB1532 exhibits excellent biocompatibility and remarkable targeting capability towards M1 macrophages with its targeting advantage notably accentuated under high shear forces. Furthermore, it significantly downregulates telomerase activity. Metabolomics analysis indicates that the decrease in telomerase activity upregulates the expression of aspartic acid, a key protein in the Caspase pathway of apotosis. In vivo, Ab-MMB1532 efficiently targeted and accumulated within AS lesions, leading to significantly delay of the AS progression by inhibiting telomerase activity and promoting apoptosis of M1 macrophages after 4-week treatment. In summary, Ab-MMB1532 provides a new approach for potentially safer and more effective treatment of AS in the future.

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