Cell-Permeant Bioadaptors for Cytosolic Delivery of Native Antibodies: A “Mix-and-Go” Approach

Antibodies are powerful tools that may potentially find wide applications in live-cell bioimaging, disease diagnostics, and therapeutics. Their practical applications have however remained limited thus far, owing to their inability to cross the cell membrane. Existing approaches for cytosolic delive...

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Veröffentlicht in:ACS central science 2020-12, Vol.6 (12), p.2362-2376
Hauptverfasser: Du, Shubo, Liew, Si Si, Zhang, Cheng-wu, Du, Wei, Lang, Wenjie, Yao, Cassandra C. Y, Li, Lin, Ge, Jingyan, Yao, Shao Q
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container_end_page 2376
container_issue 12
container_start_page 2362
container_title ACS central science
container_volume 6
creator Du, Shubo
Liew, Si Si
Zhang, Cheng-wu
Du, Wei
Lang, Wenjie
Yao, Cassandra C. Y
Li, Lin
Ge, Jingyan
Yao, Shao Q
description Antibodies are powerful tools that may potentially find wide applications in live-cell bioimaging, disease diagnostics, and therapeutics. Their practical applications have however remained limited thus far, owing to their inability to cross the cell membrane. Existing approaches for cytosolic delivery of functional antibodies are available, but they are constantly plagued by the need for chemical/genetic modifications, low delivery efficiency, and severe endolysosomal trapping. Consequently, it is of paramount importance to develop new strategies capable of highly efficient cytosolic delivery of native antibodies with immediate bioavailability. Herein, we report a modification-free, convenient “mix-and-go” strategy for the cytosolic delivery of native antibodies to different live mammalian cells efficiently, with minimal endolysosomal trapping and immediate bioavailability. By simply mixing a cell-permeant bioadaptor (derived from protein A or TRIM21) with a commercially available off-the-shelf antibody, the resulting noncovalent complex could be immediately used for intracellular delivery of native antibodies needed in subsequent cytosolic target engagement. The versatility of this approach was successfully illustrated in a number of applications, including antibody-based, live-cell imaging of the endogenous protein glutathionylation to detect oxidative cell stress, antibody-based activation of endogenous caspase-3, and inhibition of endogenous PTP1B activity, and finally TRIM21-mediated endogenous protein degradation for potential targeted therapy. Our results thus indicate this newly developed, “mix-and-go” antibody delivery method should have broad applications in chemical biology and future drug discovery.
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title Cell-Permeant Bioadaptors for Cytosolic Delivery of Native Antibodies: A “Mix-and-Go” Approach
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