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Spatiotemporal Control of Cell–Cell Reversible Interactions Using Molecular Engineering

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The deep understanding of cell–cell interactions has shown great potential in basic research and cell-based therapy. The Peng Shi team did research about using a combination of metabolic glycan labelling and bioorthogonal click reaction to engineer cell membranes with β-cyclodextrin (β-CD) and subsequently manipulate cell behaviours via photo-responsive host-guest recognition, which is an innovative method in the field of cell-based therapy research.

Dynamic cell–cell interactions are imperative for correct cell behaviour. The failure of cell communications can cause uncontrollable cell growth and cancer. Spatiotemporal modulation of cell–cell interactions would benefit fundamental cell-behavioural studies, and allow unprecedented control of cell behaviour, as well as provide a synthetic biological method for the design of cell-based therapy.

The research team from Chinese Academy of Sciences and Jilin University firstly investigate reversible manipulation of cell assembly and disassembly with a homobifunctional cross-linking agent. Considering aptamers promising recognition elements with high binding affinity to a broad range of targets, azobenzene-labelled aptamers anchored on the cell surface act as targeting ligands and induce cell–cell adhesion. Then, photo-driven host–guest recognition affords the cell–cell adhesion a novel property of reversible assembly controlled by light. At last, a cell-based therapy was designed to illustrate an actual use.

The paper demonstrates several results of this research:

1. Cell surfaces modification with β-CD: In this research, Ac4GalNAz-treated cells successfully expressed cell surface–associated azide groups. Then, the successful β-CD modification and the ability of β-CD moiety to include guests are conformed. Besides, the photocontrolled attachment and detachment of azo-PEG-SiNP confirmed the successful presentation of β-CD on cell surface.

2. Reversible manipulation of cell assembly and disassembly: this research demonstrated the homo-bifunctional cross-linking agent served as reversible cell glues could induce adhesion and aggregation of β-CD-modified cells. Cell assembly and disassembly could be reversibly manipulated with light irradiation, and the cell binding was attributed to supramolecular interactions.

3. Heterotypic cell adhesion and cell-based therapy: β-CD-labeled Hela cells could be modified with azo-aptamer and used for cell–cell adhesion. This method exhibited obvious advantage over the previous reported irreversible effects, in which the altered structure could not be reused. In addition, an actual use by applying this method toward directing peripheral blood mononuclear cells (PBMCs) to induce target cell apoptosis was illustrated—compared with unmodified PBMCs, aptamer-modified PBMCs could effectively adhere to the target MCF-7 cells and form T cells–cancer cells assembly, which means that aptamer-modified PBMCs showed enhanced cytotoxicity to MCF-7 cells.

This research demonstrates reversible manipulation of cell assembly and disassembly, which enables light-controllable reversible assembly of cell–cell adhesion, in contrast with previously reported irreversible effects. The researchers also illustrate the utility of the method by designing a cell-based therapy—PBMCs modified with aptamer are effectively redirected towards target cells, resulting in enhanced cell apoptosis. This approach allows unprecedented control of cell behaviour and benefit studies of contact-dependent cell-cell communications.

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