Matrix stiffness regulates lipid nanoparticle-mRNA delivery in cell-laden hydrogels.
Matrix stiffness regulates lipid nanoparticle-mRNA delivery in cell-laden hydrogels.
复制标题
基质刚度调节脂质纳米粒子-mRNA在充满细胞的水凝胶中的传递。
DOI：
10.1016/j.nano.2022.102550
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发表时间：
2022-06
影响因子：
5.4
通讯作者：
Bertassoni, Luiz E.
中科院分区：
文献类型：
--
作者：
Athirasala, Avathamsa;Patel, Siddharth;Menezes, Paula P.;Kim, Jeonghwan;Tahayeri, Anthony;Sahay, Gaurav;Bertassoni, Luiz E.
mRNA疗法越来越受欢迎，主要是由于蛋白质表达的瞬时和快速性质以及脱靶效应的低风险。随着针对COVID-19的基于mRNA的疫苗的显著成功，这种情况急剧增加。尽管基于脂质纳米颗粒（LNP）的递送取得了进展，但调节mRNA的有效内吞运输和翻译的机制仍然知之甚少。尽管人们广泛认为细胞外基质（ECM）调节外源性纳米复合遗传物质的摄取和表达，但尚未研究其对mRNA递送和表达的具体影响。在这里，我们证明了基质刚度在调节mRNA转染和表达中的关键作用，并通过RhoA介导的mTOR信号传导和细胞骨架动力学揭示了mRNA内吞作用的不同机械调节机制。我们的研究结果对有效地将治疗性mRNA递送到可能受组织和基质硬度差异影响的靶组织具有意义。(A)基质硬度通过（B）两种不同的调节机制调节脂质纳米颗粒-mRNA的转染和表达。
mRNA therapeutics have increased in popularity, largely due to the transient and fast nature of protein expression and the low risk of off-target effects. This has increased drastically with the remarkable success of mRNA-based vaccines for COVID-19. Despite advances in lipid nanoparticle (LNP)-based delivery, the mechanisms that regulate efficient endocytic trafficking and translation of mRNA remain poorly understood. Although it is widely acknowledged that the extracellular matrix (ECM) regulates uptake and expression of exogenous nano-complexed genetic material, its specific effects on mRNA delivery and expression has not yet been examined. Here, we demonstrate a critical role for matrix stiffness in modulating both mRNA transfection and expression and uncover distinct mechano-regulatory mechanisms for endocytosis of mRNA through RhoA mediated mTOR signaling and cytoskeletal dynamics. Our findings have implications for effective delivery of therapeutic mRNA to targeted tissues that may be differentially affected by tissue and matrix stiffness. (A) Matrix stiffness regulates the transfection and expression of lipid nanoparticle-mRNA through (B) two distinct regulatory mechanisms.
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影响因子：
14.9
作者：
Kirschman JL;Bhosle S;Vanover D;Blanchard EL;Loomis KH;Zurla C;Murray K;Lam BC;Santangelo PJ
通讯作者：
Santangelo PJ
DOI：
10.1038/s41578-021-00358-0
发表时间：
2021
期刊：
Nature reviews. Materials
影响因子：
--
作者：
Hou X;Zaks T;Langer R;Dong Y
通讯作者：
Dong Y
机械敏感的miRNA偏置通过MTOR信号传导人类间充质干细胞命运。
影响因子：
16.6
作者：
Frith JE;Kusuma GD;Carthew J;Li F;Cloonan N;Gomez GA;Cooper-White JJ
通讯作者：
Cooper-White JJ
影响因子：
41.2
作者：
Kong, HJ;Liu, JD;Mooney, DJ
通讯作者：
Mooney, DJ
影响因子：
17.1
作者：
Rehman, Zia Ur;Hoekstra, Dick;Zuhorn, Inge S.
通讯作者：
Zuhorn, Inge S.