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Dernière publication 01/01/2026

Engineered nanoconjugates for simultaneous detection and degradation of stroke-a

Our findings highlight several advantages of IO@PDA@tPA compared to free r-tPA. At 2.5 mg/kg, IO@PDA@tPA achieved similar lesion size reduction and...

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    [title] => Engineered nanoconjugates for simultaneous detection and degradation of stroke-a
    [paragraph] => Engineered nanoconjugates for simultaneous detection and degradation of stroke-associated microthrombi
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Authors
Audrey Picot, Charlène Jacqmarcq, Célia Seillier, Sara Martinez de Lizarrondo, Maxime Gauberti, Ankita Talukdar, Igor Khalin, Clarisse Mouriaux, Pierre Mangin, Didier Goux, Peter Schmidt, Denis Vivien, Thomas Bonnard

 Lab

Journal
Theranostics
Abstract
Our findings highlight several advantages of IO@PDA@tPA compared to free r-tPA. At 2.5 mg/kg, IO@PDA@tPA achieved similar lesion size reduction and vascular recanalization as 10 mg/kg of free r-tPA, representing a fourfold dose reduction that could lower the risk of systemic hemorrhagic complications. The fibrinogen-enriched protein corona enabled thrombus-specific accumulation, as confirmed by MRI, immunohistochemistry, and microfluidic assays, whereas free r-tPA lacks targeting capacity and acts systemically. IO@PDA@tPA treatment was also associated with balanced immune profiles, in contrast to IO@PDA alone, and IO@PDA particles did not increase ROS production in primary neurons under OGD, indicating neuronal compatibility. Despite these advantages, several limitations remain. Variability in lesion size and functional outcome was observed across treatment groups, both in non-diabetic and diabetic cohorts. This variability likely reflects intrinsic heterogeneity of the thrombin MCAO model, including differences in occlusion severity, collateral circulation, and reperfusion dynamics, which are further amplified in diabetic mice due to vascular dysfunction and inflammatory priming. Moreover, while IO@PDA@tPA at 5 mg/kg was safe and effective, the absence of a strict dose-response relationship suggests biological saturation. Once fibrin availability or local enzymatic activity at the clot site is maximally engaged, increasing the dose may not provide further benefit, and could instead contribute to variability through local dispersion or off-target interactions, even though we did not observe hemorrhagic transformation or toxicity at the highest tested dose. In addition, as suggested by our immune profiling, subtle immunomodulatory effects at higher doses could also influence outcomes, particularly in diabetic mice where immune dysregulation is prominent. IO@PDA@tPA is a complex multifunctional nanoconjugate requiring rigorous physicochemical characterization, reproducibility, and scalability before clinical translation, unlike free r-tPA which is already approved and widely available. Furthermore, IO@PDA clearance from liver and spleen is slower than the systemic clearance of free r-tPA, which may raise regulatory considerations, although no toxicity was observed in our models. Importantly, both PDA and IO are known to be biodegradable: PDA undergoes slow oxidative degradation through macrophage processing, while IO nanoparticles are metabolizedviaendogenous iron pathways. In line with our previous work16,20, we observed transient liver and spleen accumulation without toxicity, further supporting the favorable biocompatibility of IO@PDA@tPA. Finally, while the benefits of IO@PDA@tPA are well documented, the precise mechanisms underlying immune modulation and thrombus targeting require further investigation, including studies in larger animal models and in the context of hemorrhagic risk.
Keywords/Topics
microfluidic assays; diabetic mice; biological saturation; local enzymatic activity; regulatory considerations; our models; larger animal models; engineered nanoconjugates; simultaneous detection; degradation
BIOSEB Instruments Used:
Grip strength test (BIO-GS4)
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Une méthode simple pour quantifier objectivement la force musculaire des rats et souris et l'effet de drogues, toxines, maladies musculaires (ex: myopathie) et neurodégénératives. Cette mesure de force est souvent employée en association avec le test de coordination motrice ROTAROD: un sujet présentant une coordination normale montrera des résultats médiocres en cas de faible force musculaire. Un must pour vos recherches sur l'activité, la coordination et le contrôle musculaire: particulièrement utile pour vos études sur les maladies de Parkinson et Huntington.
Nouveautés GS4 - 2023: Écran couleur rétroéclairé (meilleure lisibilité), pédale de remise à zéro, durée de batterie optimisée, taille de mémoire augmentée à 500 valeurs, compteur d'animaux, port USB (transfert de données/charge)

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