Targeted inflammatory microenvironment remodeling and NIR-II photothermal therapy for abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a degenerative aortic disease with high rupture-associated mortality. There is no effective medical therapy for early intervention, inflammatory microenvironment remodeling is a crucial therapeutic strategy. Herein, we designed a multifunctional nanoplatform, Cu 9 S 8 @MCC950-Belnacasan-cRGDfK (CS@MBR) for AAA treatment. This platform employed a Cu 9 S 8 core for near-infrared-II (NIR-II) photothermal therapy (PTT), encapsulated NLRP3 inflammasome inhibitors (MCC950 and Belnacasan), and coated with a cRGDfK peptide for active targeting of the aneurysm. In vitro, CS@MBR with mild PTT inhibited NLRP3 inflammasome activation, decreased pro-inflammatory macrophage polarization, and prevented the phenotype switching of vascular smooth muscle cells. In vivo, CS@MBR demonstrated excellent accumulation at the aneurysm site in an angiotensin-II-induced murine AAA model. Upon NIR-II irradiation, the treatment effectively inhibited AAA development, damage of elastic fibers, and imbalance of the inflammatory microenvironment. This study presents a promising, targeted nanotherapeutic strategy for the treatment of AAA and other inflammatory vascular diseases. • We designed a nanoplatform Cu9S8@MCC950-Belnacasan-cRGDfK, which employed Cu 9 S 8 , loaded with NLRP3 inflammasome inhibitors, and coated with a targeting peptide cRGDfK. Both in vitro and in vivo, CS@MBR PTT inhibited NLRP3 inflammasome activation, decreased pro-inflammatory macrophage polarization, and prevented the phenotypic switching of VSMCs, resulting in effective prevention of AAA development. Making it a promising therapy for the treatment of AAA and inflammatory vascular diseases.