Pathogenesis-Guided Rational Engineering of Nanotherapies for the Targeted Treatment of Abdominal Aortic Aneurysm by Inhibiting Neutrophilic Inflammation

Abstract

Abdominal aortic aneurysm (AAA) remains a fatal disease in the elderly. Currently, no drugs can be clinically used for AAA therapy. Considering the pivotal role of neutrophils in the pathogenesis of AAA, herein we propose the targeted therapy of AAA by site-specifically regulating neutrophilic inflammation. Based on a luminol-conjugated α-cyclodextrin material (LaCD), intrinsically anti-inflammatory nanoparticles (NPs) were engineered by simple nanoprecipitation, which were examined as a nanotherapy (defined as LaCD NP). After efficient accumulation in the aneurysmal aorta and localization in pathologically relevant inflammatory cells in rats with CaCl 2 -induced AAA, LaCD NP significantly alleviated AAA progression, as implicated by the decreased aortic expansion, suppressed elastin degradation, inhibited calcification, and improved structural integrity of the abdominal aorta. By functionalizing LaCD NP with alendronate, a calcification-targeting moiety, the in vivo aneurysmal targeting capability of LaCD NP was considerably enhanced, thereby affording significantly potentiated therapeutic outcomes in AAA rats. Mechanistically, LaCD NP can effectively inhibit neutrophil-mediated inflammatory responses in the aneurysmal aorta. Particularly, LaCD NP potently attenuated the formation of neutrophil extracellular traps (NETs), thereby suppressing NETs-mediated pro-inflammatory events and NETosis-associated negative effects responsible for AAA progression. Consequently, we demonstrated the effectiveness and underlying mechanisms of anti-NETosis nanotherapies for the targeted treatment of AAA. Our findings provide promising insights into discovering precision therapies for AAA and other inflammatory vascular diseases.

Neutrophil Extracellular Traps in Cardiovascular and Aortic Disease: A Narrative Review on Molecular Mechanisms and Therapeutic Targeting

“…The standardization of preclinical models and of NET detection protocols are further steps on the way to the first clinical trials of NET-targeting therapies and biomarkers as reliable tools for clinical decision-making in CVD. Several promising steps towards improved and highly-specific anti-NET drug design have been taken [99,101,133]. The repurposing of already approved drugs that have been found to target NETs, such as DNase 1 [120,121] or disulfiram [134], might expedite clinical translation.…”

The role of transcription factors in the pathogenesis and therapeutic targeting of vascular diseases

“…The innate immune response will continue to be a prominent area of research in the future, given the extensive repertoire of TFs associated with inflammatory response. Neutrophils play a pivotal role in the innate immune response, and neutrophil extracellular traps (NETs) have garnered increasing attention as a crucial pathological process in aneurysm-related research ( 92 , 93 ). However, there remains a dearth of research on TFs in this context.…”