Artificial lipids and macrophage membranes coassembled biomimetic nanovesicles for thoracic aortic dissection treatment

Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease characterized by rapid progression and high morbidity. Current efforts to develop effective treatment strategies focus on targeting apoptotic aortic endothelial cells and mitigating inflammation. Here, inspired by the inflammation-neutralizing capacity of functional cells, we present multifunctional biomimetic nanovesicles (MM-LPs) co-assembled from macrophage membranes and synthetic lipids for the targeted delivery of Senkyunolide I (SEI) in TAD treatment. The integration of macrophage membranes endows MM-LPs with the ability to selectively target activated vascular endothelial cells (VECs) while adsorbing proinflammatory cytokines to suppress inflammation. Additionally, these nanoparticles enable the controlled release of SEI, leading to significant anti-apoptotic effects. Leveraging these advantages, MM-LPs effectively mitigated VEC activation, reduced apoptosis, and prevented disease progression and rupture in a BAPN-induced mouse model of TAD. Furthermore, this system significantly reduced SEI-associated toxicity and adverse effects on the liver and kidneys. These findings highlight the potential of combining natural macrophage membranes with synthetic lipids to develop a multifunctional biomimetic drug delivery system for treating VEC dysfunction while minimizing drug-related side effects. Schematic design of MM-LP@SEI NP-mediated delivery of Senkyunolide I (SEIs) to activated vascular endothelial cells (VECs) for the treatment of thoracic aortic dissection (TAD). Novel biomimetic nanovesicles (MM-LPs) combining macrophage membranes and synthetic lipids were developed for targeted senkyunolide I (SEI) delivery in thoracic aortic dissection (TAD). MM-LPs demonstrated dual functionality: specific endothelial targeting (via integrin α4β1) and immune evasion (via CD47), while adsorbing inflammatory cytokines. In TAD mice, MM-LP@SEI reduced aortic rupture through PI3K/AKT/Caspase3-mediated apoptosis inhibition and decreased inflammation, with improved safety profile. This platform offers a promising targeted therapy for TAD. • Developed hybrid MM-LP nanovesicles combining macrophage membranes with synthetic lipids, creating a multifunctional platform for TAD therapy. • Demonstrated that MM-LP@SEI selectively accumulates in aortic lesions, significantly reducing apoptosis via PI3K/AKT/Caspase3 signaling and lowering TAD incidence while preserving elastin integrity. • MM-LPs effectively adsorbed proinflammatory cytokines and reduced immune cell infiltration, addressing both vascular damage and inflammation in TAD pathogenesis. • Achieved reduced hepatic/kidney toxicity compared to free SEI, with no hemolysis or organ damage observed, highlighting the clinical potential of this biomimetic system for safe drug delivery.