Why the study?
Current antiplatelet therapies reduce thrombotic complications but cause systemic bleeding, prompting the evaluation of mRNA encoding scFv αIIbβ3 for prolonged expression, durability, and safety.
Does lipid nanoparticle-delivered mRNA encoding scFv αIIbβ3 prevent thrombosis without impairing hemostasis in preclinical models?
Does lipid nanoparticle-delivered mRNA encoding scFv αIIbβ3 prevent thrombosis without impairing hemostasis in preclinical models?
Absolute Event Rate: 24% vs 7.9%
p-value: p=<0.05
A self-amplifying mRNA therapeutic encoding a platelet-targeted scFv provides safe, continuous antithrombotic protection for over 7 days in vivo without the systemic bleeding risks characteristic of conventional antiplatelet therapies.
Hypothesis-generating for mRNA-encoded platelet-targeted antithrombotics in mice; human trials needed before any clinical consideration.
BACKGROUND: Thrombosis is a major contributor to morbidity and mortality in cardiovascular diseases. Although current antiplatelet therapies reduce thrombotic complications, they are associated with systemic bleeding complications. We previously developed a single-chain variable fragment (scFv) that specifically binds and blocks the activated platelet integrin αIIbβ3 (GPIIb/IIIa [glycoprotein IIb/IIIa]), preventing thrombosis without impairing hemostasis. We hypothesized that an mRNA-based therapeutic encoding scFv αIIbβ3 would offer prolonged expression and enhanced therapeutic durability while maintaining a favorable safety profile. METHODS: We designed and synthesized both conventional mRNA and self-amplifying mRNA constructs encoding scFv αIIbβ3 . The constructs were first validated in vitro by confirming their expression of a functional scFv αIIbβ3 . For in vivo experiments, mRNAs were encapsulated in a novel lipid nanoparticle formulation comprising of γ-oryzanol and DLin-KC2-DMA (OryKL) for systemic delivery. Their biosafety was assessed by a series of biochemical and histological examinations. The murine FeCl 3 -induced arterial thrombosis model was used to assess the preventive effect of scFv αIIbβ3 -encoding mRNAs on thrombus formation. RESULTS: In vitro assays confirmed the efficient expression and secretion of a functional scFv αIIbβ3 that selectively bound to and blocked activated GPIIb/IIIa, thereby inhibited platelet aggregation. In mice with induced thrombosis, OryKL-delivered scFv αIIbβ3 mRNA significantly prolonged occlusion time at 24 hours posttreatment, while self-amplifying mRNA provided sustained thromboprotection for over 7 days. Tail bleeding times were unchanged across all groups, and no systemic toxicity or histopathologic abnormalities were observed. CONCLUSIONS: Our findings demonstrate that scFv αIIbβ3 mRNA and self-amplifying mRNA therapeutics enable safe, effective, and long-acting antithrombotic protection in vivo, offering a promising strategy for thromboprophylaxis that prevents the bleeding risks associated with current antiplatelet therapies.
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Song et al. (2026) studied Thrombosis. scFv αIIbβ3 mRNA and self-amplifying mRNA (samRNA) vs. PBS, scFv mut mRNA, eGFP mRNA, and eptifibatide was evaluated on Carotid artery occlusion time in FeCl3-induced thrombosis model (p=<0.05).
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