Dual-targeted microbubbles for atherosclerosis therapy: Inducing M1 macrophage apoptosis by inhibiting telomerase activity

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. <i>In vivo</i> 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, <i>p</i> < 0.001). In summary, our findings suggest a novel approach for telomerase-targeted therapy in AS.