Macrophage-mimetic liposomal nanovesicles deliver CXCR2 antagonists to suppress CXCL2-driven breast cancer and atherosclerotic progression

The coexistence of breast cancer (BC) and atherosclerosis (AS) is increasingly recognized as an inflammation-driven comorbidity. This study identifies the CXCL2–CXCR2 signaling axis as a pivotal mechanistic link underlying both diseases and introduces a macrophage-mimetic nanoplatform for its targeted inhibition. Differential gene expression and PPI network analyses of GEO datasets revealed CXCL2 as a shared hub gene in BC and AS. Clinical sample analyses further showed that female BC patients with vulnerable carotid plaques or high tumor CXCL2 expression had significantly shorter overall survival and disease-free survival, and multivariate regression confirmed vulnerable carotid plaques as an independent risk factor for poor BC prognosis. Co-expression with CXCR2 was validated in murine comorbidity models, where axis activation enhanced proliferation of BC cells, migration of human carotid artery smooth-muscle cells (HCASMCs), and M2 macrophage polarization through PI3K–AKT–mTOR signaling. To selectively disrupt this pathway, we engineered macrophage membrane-coated liposomal nanovesicles loaded with the CXCR2 antagonist SB225002 (MmLip@SB). The biomimetic coating endowed inflammation-site targeting and immune-evasive properties, enabling efficient delivery to tumor and plaque regions. MmLip@SB treatment markedly reduced tumor growth, plaque burden, and inflammatory cytokine expression while improving tissue architecture. These results establish CXCL2–CXCR2 as a shared inflammatory driver of BC and AS and highlight macrophage-mimetic nanovesicles as a promising dual-acting therapeutic approach.