Nanomechanical action opens endo-lysosomal compartments

Yu Zhao, Zhongfeng Ye, Donghui Song, Douglas Wich, Shuliang Gao, Jennifer Khirallah and Qiaobing Xu ()
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Yu Zhao: Tufts University
Zhongfeng Ye: Tufts University
Donghui Song: Tufts University
Douglas Wich: Tufts University
Shuliang Gao: Tufts University
Jennifer Khirallah: Tufts University
Qiaobing Xu: Tufts University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Endo-lysosomal escape is a highly inefficient process, which is a bottleneck for intracellular delivery of biologics, including proteins and nucleic acids. Herein, we demonstrate the design of a lipid-based nanoscale molecular machine, which achieves efficient cytosolic transport of biologics by destabilizing endo-lysosomal compartments through nanomechanical action upon light irradiation. We fabricate lipid-based nanoscale molecular machines, which are designed to perform mechanical movement by consuming photons, by co-assembling azobenzene lipidoids with helper lipids. We show that lipid-based nanoscale molecular machines adhere onto the endo-lysosomal membrane after entering cells. We demonstrate that continuous rotation-inversion movement of Azo lipidoids triggered by ultraviolet/visible irradiation results in the destabilization of the membranes, thereby transporting cargoes, such as mRNAs and Cre proteins, to the cytoplasm. We find that the efficiency of cytosolic transport is improved about 2.1-fold, compared to conventional intracellular delivery systems. Finally, we show that lipid-based nanoscale molecular machines are competent for cytosolic transport of tumour antigens into dendritic cells, which induce robust antitumour activity in a melanoma mouse model.

Date: 2023
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DOI: 10.1038/s41467-023-42280-9

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