Tiered Evaluation of Carbosilane Dendrimer-siRNA Nanoplatform from Single-Cell Biocompatibility to Blood-Brain Barrier Model Dynamics and Murine Alzheimer Model Behavior Assessment.

Authors

Serafin Zawadzki, Elżbieta Okła, Sylwia Michlewska, Radosław Bednarek, Paula Ortega López, F Javier de la Mata, Juris Jansons, Dace Skrastina, Madara Kreišmane, Vladimirs Piļipenko, Baiba Jansone, Maksim Ionov, Maria Bryszewska, Katarzyna Miłowska

Published in

ACS applied materials & interfaces. Jul 06, 2026. Epub Jul 06, 2026.

Abstract

Blood-brain barrier (BBB) transport remains a primary constraint on achieving predictable central nervous system exposure for Alzheimer's disease (AD) therapeutics, motivating the evaluation of delivery platforms with barrier-resolved and functionally relevant end points. We assessed a carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex using a tiered, upstream strategy spanning cell internalization, DNA damage screening, BBB model integrity and permeability, and in vivo AD-relevant murine model learning. At the cellular level, the dendrimer enhanced intracellular siRNA-associated signal with predominantly cytoplasmic localization, and siRNA complexation attenuated genotoxicity relative to the noncomplexed carrier. In a BBB triculture model, barrier function was preserved without sustained transendothelial electrical resistance (TEER) loss, and complementary tracer flux readouts showed time- and formulation-dependent, nonmonotonic changes, including TEER-permeability decoupling consistent with nonuniform perturbation and time-dependent changes in barrier-associated paracellular responses. In APOE4 knock-in mice, dendriplex treatment increased platform-zone crossings in the Morris Water Maze probe trial, whereas target-quadrant time showed only a modest, nonsignificant trend. Collectively, these integrated results indicate that siRNA complexation improves the BBB-relevant safety-performance balance of G3Si PEG6000 and supports further studies that directly link brain exposure and target engagement to cognitive outcomes.

PMID:
42406649
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

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