DNA-functionalized artificial mechanoreceptor for de novo force-responsive signaling.

Sihui Yang, Miao Wang, Dawei Tian, Xiaoyu Zhang, Kaiqing Cui, Shouqin Lü, Hong-Hui Wang, Mian Long, Zhou Nie

Nature chemical biology 2024 Aug

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Synthetic signaling receptors enable programmable cellular responses coupling with customized inputs. However, engineering a designer force-sensing receptor to rewire mechanotransduction remains largely unexplored. Herein, we introduce nongenetically engineered artificial mechanoreceptors (AMRs) capable of reprogramming non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, enabling de novo-designed mechanotransduction. AMR is a modular DNA-protein chimera comprising a mechanosensing-and-transmitting DNA nanodevice grafted on natural RTKs via aptameric anchors. AMR senses intercellular tensile force via an allosteric DNA mechano-switch with tunable piconewton-sensitive force tolerance, actuating a force-triggered dynamic DNA assembly to manipulate RTK dimerization and activate intracellular signaling. By swapping the force-reception ligands, we demonstrate the AMR-mediated activation of c-Met, a representative RTK, in response to the cellular tensile forces mediated by cell-adhesion proteins (integrin, E-cadherin) or membrane protein endocytosis (CI-M6PR). Moreover, AMR also allows the reprogramming of FGFR1, another RTK, to customize mechanobiological function, for example, adhesion-mediated neural stem cell maintenance. © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Sihui Yang, Miao Wang, Dawei Tian, Xiaoyu Zhang, Kaiqing Cui, Shouqin Lü, Hong-Hui Wang, Mian Long, Zhou Nie. DNA-functionalized artificial mechanoreceptor for de novo force-responsive signaling. Nature chemical biology. 2024 Aug;20(8):1066-1077