Bian Shuang, Zhu Yangang, Zhao Nanxin, Wang Yanchen, Yang Zhimou, Li Jingjing
School of Medical Imaging, Xuzhou Medical University, Xuzhou, 221004, People's Republic of China.
Department of Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, People's Republic of China.
Mater Today Bio. 2025 May 1;32:101827. doi: 10.1016/j.mtbio.2025.101827. eCollection 2025 Jun.
Atherosclerosis (AS) is characterized by lipid overaccumulation and progressive chronic inflammation. Macrophages over-accumulate at plaque sites and promote fibrous cap instability and plaque rupture by participating in lipoprotein uptake and metabolism, inflammatory factor secretion, and the production of enzymes and toxic metabolites. The macrophages accumulating at plaque sites are mainly derived from circulating blood-derived monocytes. Therefore, we designed a peptide 2P with an alkaline phosphatase (ALP) induced self-assembly function and P-selectin targeting function to form a supramolecular bi-antibodies 2P@VLA-4 by coassembling with VLA-4, a CD106 affinity. The dephosphorylation site and efficiency were optimized. 2P@VLA-4 displayed enhanced protein stability and binding ability to inflamed vascular endothelial cells. Through the dual-targeted blocking effect on the adhesion binding site of monocytes, 2P@VLA-4 could significantly reduce the accumulation of monocytes/macrophages at the plaque site, thereby inhibiting the progression of AS. At the same time, modification of peptides with fluorescent molecules enabled specific imaging of plaques. This study focused on the ease of design and functionalization of peptides, to synthesize supramolecular bi-antibodies compound innovatively by enzyme instructed self-assembly (EISA), achieving the significant inhibition of the adhesion and aggregation of monocytes at plaque sites. Coupling with its specific imaging capability, it may provide new approaches for the integrated design of diagnosis and treatment of AS
动脉粥样硬化（AS）的特征是脂质过度积累和进行性慢性炎症。巨噬细胞在斑块部位过度积累，并通过参与脂蛋白摄取与代谢、炎症因子分泌以及酶和有毒代谢产物的产生，促进纤维帽不稳定和斑块破裂。在斑块部位积累的巨噬细胞主要来源于循环血液中的单核细胞。因此，我们设计了一种具有碱性磷酸酶（ALP）诱导自组装功能和P-选择素靶向功能的肽2P，通过与具有CD106亲和力的VLA-4共组装形成超分子双抗体2P@VLA-4。对去磷酸化位点和效率进行了优化。2P@VLA-4表现出增强的蛋白质稳定性以及与炎症血管内皮细胞的结合能力。通过对单核细胞黏附结合位点的双靶点阻断作用，2P@VLA-4可显著减少单核细胞/巨噬细胞在斑块部位的积累，从而抑制AS的进展。同时，用荧光分子修饰肽可实现斑块的特异性成像。本研究聚焦于肽的设计简便性和功能化，通过酶指导自组装（EISA）创新地合成超分子双抗体化合物，实现对单核细胞在斑块部位黏附和聚集的显著抑制。结合其特异性成像能力，可为AS的诊断与治疗一体化设计提供新途径。
