AntagomiR-155 hitchhiking on biomimetic yeast microcapsules alleviate atherosclerosis by inhibiting M1-like macrophages.

Atherosclerosis progression is driven by the plasticity of plaque macrophages, making the suppression of M1-like macrophage polarization a promising therapeutic goal. While inhibiting the M1-regulator microRNA-155 (miR-155) is a viable strategy, its clinical application is limited with inadequate systemic bioavailability and off-target organ damage. Herein, we developed YC/ANM-155, an orally delivered biomimetic system that utilizes yeast microcapsules (YC) to specifically transport AntagomiR-155 (ANM-155) to aortic plaques. This targeted strategy demonstrated superior efficacy compared to free ANM-155 in alleviating the atherosclerotic burden. Mechanistically, the treatment suppressed local miR-155 expression, inhibited M1-like macrophage polarization, and downregulated key pro-inflammatory cytokines at both the lesional and systemic levels. Complementary in vitro studies showed that miR-155 inhibition reduced M1-like macrophage polarization and attenuated inflammatory activation. The formulation showed improved stability under simulated gastrointestinal conditions and favorable biosafety under the present experimental settings. Collectively, our findings suggest that yeast-mediated oral delivery of miRNA antagomirs may serve as a promising preclinical strategy for RNA-based AS therapy and warrant further evaluation in larger-scale preclinical models.