An Extravascular Synergistic Cocktail Therapeutic Strategy Based on Lanifibranor Loaded Self-Healing Bioelastomer for...

Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disease with hidden onset and high risk of rupture death, which is a major public health concern worldwide. Notably, aortic adventitia is the earliest lesions and the last barrier to rupture, and adventitial fibroblasts (AFs) are the key cellular components of aortic adventitia. Current treatments mainly focus on surgical resection with prosthetic graft replacement and endovascular stent grafting, yet failed to reconstruct the adventitia and abdominal aorta's natural structure effectively. In this study, we proposed an extravascular synergistic cocktail (ESC) therapeutic strategy to treat AAA by incorporating mechanical supporting and vascular remodeling inhibition based on a self-healing bioelastomer with antifibrotic drug of lanifibranor. The single-cell RNA-sequencing revealed potential myogenic transformation of AFs in AAA with the release of chemokines like monocyte chemoattractant protein-1 (MCP-1). The underlying mechanism of lanifibranor in maintaining the phenotype of AFs via promoting lipid metabolism was disclosed. The bioelastomer with multiple reversible dynamic bonds exhibits remarkable arterial-like mechanical properties and ultra-fast self-healing ability under blood condition, and enables rapid in situ AAA wrapping treatment. In both the rat and dog AAA models, it has been fully demonstrated that the ESC therapy can provide effective mechanical support to prevent vascular dilation while continuously releasing lanifibranor to regulate myogenic transformation of AFs to inhibit the development of AAA. Additionally, we investigated the feasibility of minimally invasive laparoscopic implantation in bama pigs, emphasizing its potential for clinical translation and application.