Targeted GLP-1 nanotherapy for Wnt/β-catenin activation to enhance endothelial progenitor cell-mediated re-endothelialization and prevent intracranial aneurysm recurrence.

Abstract

Intracranial aneurysm (IA) is a leading cause of subarachnoid hemorrhage, characterized by complex pathogenesis and high mortality rates due to rupture. The aim of this study was to develop a targeted glucagon-like peptide-1 (GLP-1) nanodelivery system to mobilize endothelial progenitor cells (EPCs) and enhance re-endothelialization in a rat model of coiled IA. In this study, a matrix metalloproteinase-2 (MMP-2)-targeted nanodelivery platform (hereafter GLP-1@tMSN [targeted mesoporous silica nanoparticle]) based on MSNs functionalized with GLP-1 was developed to mobilize EPCs and accelerate vascular repair. The efficacy of GLP-1@tMSN in promoting EPC recruitment and re-endothelialization was evaluated in a rat coiled aneurysm model, alongside mechanistic studies of the Wnt/β-catenin signaling pathway. In a rat model of coiled IA, GLP-1@tMSN significantly enhanced the recruitment of EPCs and promoted re-endothelialization. Histological analysis demonstrated the formation of mature endothelial-like tissue after 28 days, in contrast to the fibrous tissue observed in the control group. Immunofluorescence analysis confirmed the preferential accumulation of CD34+VEGFR2+ EPCs at the lesion site, with concurrent activation of the Wnt/β-catenin pathway, implicating its pivotal role in driving vascular repair. Preliminary safety evaluations further indicated a favorable biocompatibility profile for the nanotherapeutic system. The developed functionalized nanodelivery platform represents a promising therapeutic strategy to enhance localized GLP-1 efficacy, facilitating rapid re-endothelialization and potentially reducing long-term recurrence of IAs after embolization. This approach shows substantial potential for improving outcomes for patients with IA.