Synthetic Artificial Apoptosis‐Inducing Receptor for On‐Demand Deactivation of Engineered Cells

Monge, Pere; Løvschall, Kaja Borup; Søgaard, Ane Bretschneider; Walther, Raoul; Golbek, Thaddeus W.; Schmüser, Lars; Weidner, Tobias; Zelikin, Alexander N.

doi:10.1002/advs.202004432

Cited by 5 publications

(2 citation statements)

References 37 publications

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“…Self-immolative linkers (SILs) enable stimuli-responsive traceless drug release from a prodrug in response to an activator, which can be physical, chemical, or biochemical (enzymatic), and are highly successful in both academia and in industry 29 – 34 . In our recent work, we designed cell surface-anchored prodrugs as artificial apoptosis-inducing receptors: exofacial activation of the prodrug ensued decomposition of the SIL and release of the secondary messenger molecule, which was a potent toxin 35 . These results led us to recognize that SILs can serve as a chemical mechanism for signal transduction across sealed biological membranes, thus addressing the challenge of receptor mimicry in syncells.…”

Section: Introductionmentioning

confidence: 99%

Transmembrane signaling by a synthetic receptor in artificial cells

et al. 2023

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Signal transduction across biological membranes is among the most important evolutionary achievements. Herein, for the design of artificial cells, we engineer fully synthetic receptors with the capacity of transmembrane signaling, using tools of chemistry. Our receptors exhibit similarity with their natural counterparts in having an exofacial ligand for signal capture, being membrane anchored, and featuring a releasable messenger molecule that performs enzyme activation as a downstream signaling event. The main difference from natural receptors is the mechanism of signal transduction, which is achieved using a self-immolative linker. The receptor scaffold is modular and can readily be re-designed to respond to diverse activation signals including biological or chemical stimuli. We demonstrate an artificial signaling cascade that achieves transmembrane enzyme activation, a hallmark of natural signaling receptors. Results of this work are relevant for engineering responsive artificial cells and interfacing them and/or biological counterparts in co-cultures.

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Section: Introductionmentioning

confidence: 99%

Transmembrane signaling by a synthetic receptor in artificial cells

et al. 2023

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“…Sum frequency scattering (SFS) vibrational spectroscopy can overcome these limitations and is truly ideal to provide this information and is a powerful technique that is capable to provide surface molecular structure of lipid nanosurfaces. SFS is a vibrational coherent surface spectroscopy that provides information on molecular order, orientation, and chemical composition of interfacial molecules located on nanoparticles − and has been previously used to investigate the assembly of model peptides at nanosurfaces . Here, for the first time, we will use SFS to follow the interaction of the antimicrobial enzyme lysozyme with the surface of a solid lipid nanoparticle.…”

Section: Introductionmentioning

confidence: 99%

Lysozyme Interaction with Phospholipid Nanodroplets Probed by Sum Frequency Scattering Vibrational Spectroscopy

et al. 2023

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When a nanoparticle (NP) is introduced into a biological environment, its identity and interactions are immediately attributed to the dense layer of proteins that quickly covers the particle. The formation of this layer, dubbed the protein corona, is in general a combination of proteins interacting with the surface of the NP and a contest between other proteins for binding sites either at the surface of the NP or upon the dense layer. Despite the importance for surface engineering and drug development, the molecular mechanisms and structure behind interfacial biomolecule action have largely remained elusive. We use ultrafast sum frequency scattering (SFS) spectroscopy to determine the structure and the mode of action by which these biomolecules interact with and manipulate interfaces. The majority of work in the field of sum frequency generation has been done on flat model interfaces. This limits some important membrane properties such as membrane fluidity and dimensionalityimportant factors in biomolecule–membrane interactions. To move toward three-dimensional (3D) nanoscopic interfaces, we utilize SFS spectroscopy to interrogate the surface of 3D lipid monolayers, which can be used as a model lipid-based nanocarrier system. In this study, we have utilized SFS spectroscopy to follow the action of lysozyme. SFS spectra in the amide I region suggest that there is lysozyme at the interface and that the lysozyme induces an increased lipid monolayer order. The binding of lysozyme with the NP is demonstrated by an increase in acyl chain order determined by the ratio of the CH3 symmetric and CH2 symmetric peak amplitudes. Furthermore, the lipid headgroup orientation s-PO2 – change strongly supports lysozyme insertion into the lipid layer causing lipid disruption and reorientation. Altogether, with SFS, we have made a huge stride toward understanding the binding and structure change of proteins within the protein corona.

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Artificial Receptor in Synthetic Cells Performs Transmembrane Activation of Proteolysis

Søgaard,

Løvschall,

Montasell

et al. 2024

Advanced Biology

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The design of artificial, synthetic cells is a fundamentally important and fast‐developing field of science. Of the diverse attributes of cellular life, artificial transmembrane signaling across the biomolecular barriers remains a high challenge with only a few documented successes. Herein, the study achieves signaling across lipid bilayers and connects an exofacial enzymatic receptor activation to an intracellular biochemical catalytic response using an artificial receptor. The mechanism of signal transduction for the artificial receptor relies on the triggered decomposition of a self‐immolative linker. Receptor activation ensues its head‐to‐tail decomposition and the release of a secondary messenger molecule into the internal volume of the synthetic cell. Transmembrane signaling is demonstrated in synthetic cells based on liposomes and mammalian cell‐sized giant unilamellar vesicles and illustrates receptor performance in cell mimics with a diverse size and composition of the lipid bilayer. In giant unilamellar vesicles, transmembrane signaling connects exofacial receptor activation with intracellular activation of proteolysis. Taken together, the results of this study take a step toward engineering receptor‐mediated, responsive behavior in synthetic cells.

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Synthetic Artificial Apoptosis‐Inducing Receptor for On‐Demand Deactivation of Engineered Cells

Cited by 5 publications

References 37 publications

Transmembrane signaling by a synthetic receptor in artificial cells

Transmembrane signaling by a synthetic receptor in artificial cells

Lysozyme Interaction with Phospholipid Nanodroplets Probed by Sum Frequency Scattering Vibrational Spectroscopy

Artificial Receptor in Synthetic Cells Performs Transmembrane Activation of Proteolysis

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