Safeguarding VSMC Contractile Phenotype With In Situ circRNA‐mediated Endothelial Olaratumab Engineering to Prevent Vascular Graft Stenosis

Abstract

ABSTRACT Small‐diameter vascular grafts (SDVGs) often fail due to restenosis driven by endothelial cell (EC)‐derived PDGF‐BB, which shifts vascular smooth muscle cells (VSMCs) toward a synthetic phenotype. Despite mechanistic insights, durable, localized, and cell‐specific control of this crosstalk remains elusive. Here, we developed a circRNA‐based in situ antibody engineering strategy to functionalize SDVGs, reprogramming ECs into local biofactories that secrete Olaratumab (Ola), a PDGFR‐α‐neutralizing antibody, to precisely modulate EC‐VSMC signaling. In vitro, in situ Ola engineering reversed PDGF‐BB‐induced VSMC phenotypic switching, markedly suppressing migration, invasion, and excessive extracellular matrix deposition by attenuating MAPK and PI3K‐AKT pathways. In the rat model, this approach enabled sustained local antibody secretion for up to 24 days, accelerated endothelialization, and significantly reduced neointimal hyperplasia and graft calcification over 6 months, thereby lowering the risk of SDVG restenosis. CircRNA‐based in situ antibody engineering offers a powerful modality to modulate intercellular crosstalk and sustain the VSMC contractile phenotype.