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bioRxiv · 10.64898/2026.05.13.725039

Dual-action nanoconjugate for overcoming r-tPA -resistant clots

Picot, A.·Leboucher, M.·Helaine, C.·Talukdar, A.·Khalin, I.·Martinez de Lizarrondo, S.·Gauberti, M.·Nomenjanahary, M.·Goux, D.·Ho-Tin-Noe, B.·Vivien, D.·Bonnard, T.
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Abstract

Clot resistance to pharmacological thrombolysis remains a critical challenge in ischemic stroke (IS) management. Thrombus heterogeneity, particularly the presence of thrombolysis-resistant domains composed of dense fibrin and non-fibrin components, including neutrophil extracellular traps (NETs), significantly limits the efficacy of recombinant tissue-type plasminogen activator (r-tPA) and its variant, Tenecteplase (TNK). Consequently, novel therapeutic strategies are urgently required. Emerging evidence suggests that co-administration of deoxyribonuclease I (DNase I) with r-tPA can degrade DNA fibers and enhance clot lysis. In this study, we optimized a previously developed theranostic agent--iron oxide microparticles coated with polydopamine--by dual-grafting both r-tPA and DNase to target resistant thrombi. Using functional ultrasound imaging (fUS) during the acute phase of IS, we demonstrated accelerated reperfusion with this dual-functionalized platform in a r-tPA resistant IS model. Furthermore, MRI analysis confirmed a significant reduction in lesion volume at 24 hours, correlating with improved functional recovery five days post-ischemia.

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Picot, A., Leboucher, M., Helaine, C., Talukdar, A., Khalin, I., Martinez de Lizarrondo, S., Gauberti, M., Nomenjanahary, M., Goux, D., Ho-Tin-Noe, B., Vivien, D., Bonnard, T.. 2026-05-21. Dual-action nanoconjugate for overcoming r-tPA -resistant clots. https://doi.org/10.64898/2026.05.13.725039

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