A VAPG Incorporating Targeted Self-Assembling Peptides for Efficient VSMC Restoring and Imaging in Abdominal Aortic Models

Vascular smooth muscle cell (VSMC) dysfunction is closely associated with vascular remodeling during abdominal aortic aneurysm (AAA) progression, making VSMC repair a vital therapeutic strategy. Although peptides capable of VSMC recruitment have been reported, their application is severely limited by poor accumulation in AAA lesions because of rapid clearance following systemic administration. The enzyme-triggered self-assembling peptide strategy has emerged as a safe and effective approach to prolong local retention while enabling specific responsiveness. In this study, we identified ADAMTS4 and MMP-2 as highly expressed proteases in AAA lesions, serving as ideal targets for in situ retention. We developed a Targeted Responsive Assembly Peptide (TRAP) strategy by incorporating the VSMC-recruitment peptide VAPG, an ADAMTS4 recognition motif for AAA targeting, and an MMP-2-responsive cleavage motif that triggers self-assembly of the Fmoc-FF fragment. Following enzymatic activation, VAPG-containing fragments undergo self-assembly into hydrogels, significantly enhancing VSMC recruitment. The secondary structure transitioned from random coils to β-sheets upon MMP-2 cleavage. The assembled hydrogels exhibited moderate viscoelastic behavior, with stable elastic properties, favorable mechanical strength, and shear resistance. Moreover, PET/CT imaging revealed that 68Ga-labeled peptide enables non-invasive monitoring of peptide accumulation and retention at AAA sites. Ultimately, this TRAP strategy potentially serves as an efficient approach for AAA treatment through long-acting VSMC repair.