<p>Atherosclerosis is a complex pathology driven by chronic inflammation, lipid accumulation, and thrombosis, necessitating multi-pathway therapeutic strategies. Herein, we engineered an oral multi-stage platform (RALM) comprising aspirin (Asp) and ginsenoside Rg3 co-loaded phosphatidylserine (PS) liposomes (RA-Lipo) encapsulated within sodium alginate microspheres. Physicochemical and biological evaluations revealed that the incorporation of Rg3 into the lipid bilayer as a cholesterol substitute yielded uniform RA-Lipo, which exhibited colloidal stability, intestinal epithelial transport, and prolonged systemic circulation. The electrosprayed alginate matrix functioned as a pH-responsive barrier, preventing premature degradation in the gastric environment and enabling the sustained release of RA-Lipo within the intestinal tract. Following oral administration in HFD-induced ApoE^−/− mice, integrated 16&#xa0;S rRNA sequencing and untargeted metabolomics revealed that RALM reshaped HFD-induced dysbiosis and modulated the metabolic profile, characterized by an increased <i>Bacteroidetes/Firmicutes</i> (B/F) ratio along with decreased prostaglandin E2 (PGE2) and elevated arginine levels. Fluorescence tracking experiment further demonstrated that the liberated RA-Lipo accumulated within aortic plaques. At the cellular level, RA-Lipo activated the PPARγ pathway, thereby enhancing cholesterol efflux and inhibiting foam cell formation. Ultimately, this synergistic regulation translated into remarkable therapeutic efficacy, effectively reducing plaque burden, suppressing pro-inflammatory cytokines, and demonstrating superior anticoagulant activity. Supported by a favorable safety evaluation, this RALM platform offers a comprehensive approach for alleviating atherosclerosis progression.</p> Graphical Abstract <p></p>