Engineered Hybrid Nanovesicles Combining Macrophage Membranes and Artificial Lipids for Abdominal Aortic Aneurysm Therapy.

Background and Aims: Abdominal aortic aneurysm (AAA) is a vascular condition with high mortality for which no pharmacological treatments have been approved. Targeting endothelial dysfunction as a primary disease initiator, the vascular endothelial cell (VEC)- protective compound Senkyunolide I (SEI) demonstrates therapeutic promise through robust antiapoptotic activity. Nevertheless, SEI's clinical translation faces limitations due to systemic toxicity, necessitating development of safer therapeutic alternatives. Results: This study presents an engineered biomimetic nanoplatform (Lipo-MM nanoparticles) combining macrophage-derived membranes with synthetic lipid bilayers for targeted SEI delivery. The macrophage membrane component facilitates precise targeting of activated VECs, while optimized artificial membrane fluidity enhances nanoparticle stability. This dual-membrane configuration enables sustained SEI release with enhanced biodistribution, achieving superior cytoprotective effects. Notably, we established a novel fusion membrane delivery system (Lipo-MM/SEI) and validated its therapeutic efficacy in angiotensin II-challenged AAA murine models. The nanocarrier significantly attenuated AAA progression, reflected by decreased 40% of AAA incidence, 31.4% of maximum aortic diameter, reduced elastin degradation and prevented fatal rupture events. Furthermore, Lipo-MM/SEI administration substantially reduced hepatorenal toxicity associated with free SEI administration during chronic treatment. Conclusion: These results demonstrate that hybrid biomimetic systems integrating natural cellular components with engineered materials offer a strategic approach for vascular endothelial repair therapy while minimizing off-target effects. This membrane fusion technology establishes a prototype for developing next-generation targeted vascular therapeutics.