Self‐Assembled and Size‐Controllable Oligonucleotide Nanospheres for Effective Antisense Gene Delivery through an Endocytosis‐Independent Pathway

Zhou, Jie; Sun, Liqin; Wang, Liping; Liu, Yichang; Li, Jinyu; Li, Jingying; Li, Juan; Yang, Huang‐Hao

doi:10.1002/ange.201813665

Cited by 27 publications

(11 citation statements)

References 41 publications

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“…Such observations had also been reported previously in other antibody delivery systems by using IgG-binding proteins genetically fused with CPPs, 17 , 38 as well as in some CPD-mediated biomolecular delivery systems. 22 , 24 , 27 , 28 This phenomenon is atypical, as in other protein delivery systems, where green fluorescent protein (GFP) was typically used as cargo, diffuse fluorescence signals could be observed upon successful cytosolic delivery. 6 , 13 We noted, however, this punctate fluorescent signal pattern was reminiscent of nanoparticle-based protein delivery systems.…”

Section: Resultsmentioning

confidence: 99%

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

Liew

Zhang

et al. 2020

ACS Cent. Sci.

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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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Section: Resultsmentioning

confidence: 99%

“…Notwithstanding such shortcomings, various strategies based on CPDs and their derivatives for intracellular biomolecular delivery have become increasingly popular in recent years. 27 − 29 …”

Section: Introductionmentioning

confidence: 99%

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

Liew

Zhang

et al. 2020

ACS Cent. Sci.

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“… 72 Gene transfection with CPDs obtained by templated polymerization has also been confirmed in a most elegant study by Yang, Li, and co-workers (see section 5.5 ). 83 …”

Section: Privileged Scaffoldsmentioning

confidence: 99%

Thiol-Mediated Uptake

Laurent

Martinent

Lim

et al. 2021

JACS Au

112

208

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This Perspective focuses on thiol-mediated uptake, that is, the entry of substrates into cells enabled by oligochalcogenides or mimics, often disulfides, and inhibited by thiol-reactive agents. A short chronology from the initial observations in 1990 until today is followed by a summary of cell-penetrating poly(disulfide)s (CPDs) and cyclic oligochalcogenides (COCs) as privileged scaffolds in thiol-mediated uptake and inhibitors of thiol-mediated uptake as potential antivirals. In the spirit of a Perspective, the main part brings together topics that possibly could help to explain how thiol-mediated uptake really works. Extreme sulfur chemistry mostly related to COCs and their mimics, cyclic disulfides, thiosulfinates/-onates, diselenolanes, benzopolysulfanes, but also arsenics and Michael acceptors, is viewed in the context of acidity, ring tension, exchange cascades, adaptive networks, exchange affinity columns, molecular walkers, ring-opening polymerizations, and templated polymerizations. Micellar pores (or lipid ion channels) are considered, from cell-penetrating peptides and natural antibiotics to voltage sensors, and a concise gallery of membrane proteins, as possible targets of thiol-mediated uptake, is provided, including CLIC1, a thiol-reactive chloride channel; TMEM16F, a Ca-activated scramblase; EGFR, the epithelial growth factor receptor; and protein-disulfide isomerase, known from HIV entry or the transferrin receptor, a top hit in proteomics and recently identified in the cellular entry of SARS-CoV-2.

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“…Thiol‐mediated uptake is an intriguing process because it works so well but is so poorly understood [1] . The ability of oligochalcogenides, usually disulfides, to facilitate cell penetration has been observed in many variations [2–14] . The unifying theme is dynamic covalent oligochalcogenide exchange with thiols (and/or disulfides) on the cell surface that can be inhibited by thiol reactive agents ( Figure 1 ,a ).…”

Section: Figurementioning

confidence: 99%

Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

Lim

Cheng

Kato

et al. 2021

Helvetica Chimica Acta

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Thiol‐mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol‐mediated uptake. High‐content high‐throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol‐mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super‐cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol‐mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol‐mediated uptake is of general interest for the discovery of new antivirals.

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Self‐Assembled and Size‐Controllable Oligonucleotide Nanospheres for Effective Antisense Gene Delivery through an Endocytosis‐Independent Pathway

Cited by 27 publications

References 41 publications

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

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

Thiol-Mediated Uptake

Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

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