Impact of Nanoparticle Stiffness on Endosomal Escape and Signaling Pathways in Cytosolic Delivery
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(Published version)
Date
2025
Authors
Zhang, Y.
Hui, Y.
Guo, Z.
Liu, D.
Liu, Y.
Gao, H.
Zhao, C.-X.
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Journal Title
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Volume Title
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Journal article
Citation
Advanced healthcare materials, 2025; 14(28):2501706-1-2501706-15
Statement of Responsibility
Yali Zhang, Yue Hui, Zichao Guo, Dawei Liu, Yun Liu, Huajian Gao, and Chun-Xia Zhao
Conference Name
Abstract
Viruses utilize stiffness tuning to enhance cell entry and uncoating, as cells can regulate the uptake process by sensing the mechanical stimulation of particles. The improved cytosolic delivery efficiency enhances the nanoparticle (NPs) accumulation in target sites, which is a prerequisite for achieving efficient treatment performance. However, the preparation of NPs with similar physicochemical properties but distinct stiffnesses is relatively limited, and the role of NP stiffness in intracellular distribution remains elusive. In this study, using two silica precursors at different molar ratios, silica nanocapsules (SNCs) are synthesized with a stiffness range (1.37 MPa to 1.72 GPa) spanning orders of magnitude. Additionally, an endosomal escape assay (EEA) is developed to enable rapid quantification of NP intracellular distribution based on cell fractionation. SNCs with lower stiffness exhibit superior cellular uptake efficiency. The hard SNCs however, demonstrate ≈1.8 fold-enhanced endosomal escape efficiency compared to soft SNCs. Sequencing results reveal that SNCs with higher stiffness activate the reactive oxygen species (ROS)-mediated mechanism, which facilitates rapid endosomal escape by inducing moderate oxidative stress. This work highlights the critical role of NP stiffness in regulating cytosolic delivery and the trade-off between nanotoxicity and delivery efficiency.
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Dissertation Note
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Available online 14 July 2025
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© 2025 The Author(s). Advanced Healthcare Materials published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.