Two Birds with One Stone: Targeting METTL3 Ameliorates Doxorubicin-Induced Endothelial Premature Senescence and Atherosclerosis While Potentiating Its Antitumor Efficacy

Emerging evidence suggests that cancer survivors who have undergone anthracycline therapy frequently experience late-onset atherosclerosis. However, the mechanisms underlying this phenomenon and potential preventive strategies remain largely unexplored. In this study, we developed a mouse model to replicate doxorubicin (Dox)-induced atherosclerotic lesions. Given the established role of the RNA methyltransferase METTL3 in both atherogenesis and tumorigenesis, we conducted a comprehensive investigation to assess whether targeting METTL3 could mitigate Dox-induced atherosclerosis and enhance the efficacy of Dox in inhibiting tumor progression. Our findings reveal that Dox administration promotes vascular endothelial premature senescence and atherosclerosis, to a large extent by upregulating the expression of METTL3 and its substrate genes, particularly those encoding senescence-associated secreted proteins. To translate METTL3 as a therapeutic target, we developed and characterized an endothelium-targeted (achieved by coating with CD31 antibodies) nanoparticle loaded with the METTL3 inhibitor STM2457 (endothelium-targeted METTL3 nano-inhibitor, ETMN). As anticipated, ETMN effectively protects murine blood vessels against Dox-aggravated endothelial senescence and inflammation, as well as atheroma formation. Furthermore, ETMN, with enhanced enrichment in tumor allografts, significantly potentiates Dox's tumoricidal activity by attenuating METTL3 oncogenic signaling. In summary, our work offers a practical solution for addressing Dox therapy-related atherosclerosis, providing dual benefits and advancing the treatment and management of cancer patients undergoing anthracycline therapy. This study investigates the mechanism of doxorubicin (Dox)-induced atherosclerosis in cancer survivors and develops a targeted therapeutic strategy. We reveal that Dox promotes vascular endothelial senescence and atherogenesis by upregulating the RNA methyltransferase METTL3. An endothelium-targeted METTL3 nano-inhibitor (ETMN) is shown to concurrently alleviate Dox-accelerated atherosclerosis and potentiate its anti-tumor efficacy, offering a "two birds with one stone" approach. • RNA methyltransferase METTL3 is identified as a key mediator of doxorubicin-induced endothelial senescence and atherosclerosis. • An endothelium-targeted nanoparticle (ETMN) is developed for the specific delivery of the METTL3 inhibitor STM2457 to diseased vasculature and tumors. • ETMN co-administration alleviates doxorubicin-aggravated atherosclerotic plaque formation while simultaneously enhancing its anti-tumor efficacy. • Our work provides a promising therapeutic approach to decouple the anticancer benefits of anthracyclines from their detrimental vascular side effects.