GlycoRNA-rich, neutrophil membrane-coated, siMT1-loaded nanoparticles mitigate abdominal aortic aneurysm progression by inhibiting the formation of neutrophil extracellular traps

Abdominal aortic aneurysm (AAA) is a life-threatening vascular condition. Currently, there are no clinically available pharmacological interventions that can stop the progression of AAA, primarily due to the incomplete understanding of its pathogenesis and the absence of effective drug delivery systems. The present study aimed to develop a targeted therapy for AAA through a nanomedicine approach involving site-specific regulation of neutrophil extracellular trap (NET)-related pathological vascular remodeling. We found that metallothionein 1 (MT1) was upregulated in AAA lesions in both humans and mice. MT1 also facilitated the formation of NETs and subsequently induced phenotypic transformation and apoptosis in vascular smooth muscle cells. Additional in vivo studies revealed that the glycoRNA-rich membranes coated siMT1-loaded poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) nanoparticles (GlycoRNA-NP-siMT1) effectively delivered siMT1 to AAA lesions, thereby inhibiting abdominal aortic dilation. Mechanistically, GlycoRNA-NP-siMT1 mitigated pathological remodeling of the abdominal aorta by reducing neutrophil infiltration and inhibiting the formation of NETs. Our study indicates that MT1 facilitates the progression of AAA by modulating the formation of NETs. Furthermore, GlycoRNA-NP-siMT1 show an inhibitory effect on AAA progression through a dual mechanism: they competitively inhibit neutrophil infiltration and release siMT1, which subsequently suppresses NET formation.