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Bioactive Cell-Like Hybrids from Dendrimersomes with a Human Cell Membrane and Its Components

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Bioactive Cell-Like Hybrids from Dendrimersomes with a Human Cell Membrane and Its Components Bioactive cell-like hybrids from dendrimersomes with a human cell membrane and its components Srujana S. Yadavallia,b, Qi Xiaoc,d, Samuel E. Shermanc, William D. Hasleyc, Michael L. Kleind,1, Mark Gouliana,e,1, and Virgil Percecc,1 aDepartment of Biology, University of Pennsylvania, Philadelphia, PA 19104-6313; bDepartment of Genetics, Rutgers University, Piscataway, NJ 08854; cRoy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323; dInstitute of Computational Molecular Science, Temple University, Philadelphia, PA 19122; and eDepartment of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104-6396 Contributed by Michael L. Klein, August 6, 2018 (sent for review July 2, 2018; reviewed by Ling Peng and Donald A. Tomalia) Cell-like hybrids from natural and synthetic amphiphiles provide a the monolayers containing phospholipids and block copolymer platform to engineer functions of synthetic cells and protocells. (18, 19). Also, three-component hybrid vesicles from block co- Cell membranes and vesicles prepared from human cell mem- polymer−phospholipid−glycolipid mixtures could be made (20). branes are relatively unstable in vitro and therefore are difficult to The negative aspect of this issue is that the immiscibility between study. The thicknesses of biological membranes and vesicles self- phospholipids and block copolymers does not contribute to the assembled from amphiphilic Janus dendrimers, known as dendri- stabilization of the phospholipid fragments of the hybrid vesicles, mersomes, are comparable. This feature facilitated the coassembly and therefore a continuous reorganization of the structure of of functional cell-like hybrid vesicles from giant dendrimersomes hybrid vesicles occurs (19, 21). None of these hybrid coassem- and bacterial membrane vesicles generated from the very stable blies used bacterial or mammalian cell membranes containing bacterial Escherichia coli cell after enzymatic degradation of its native components (17). Transmembrane proteins such as outer membrane. Human cells are fragile and require only mild aquaporin were incorporated in a single block copolymer- centrifugation to be dismantled and subsequently reconstituted derived polymersome rather than in a hybrid phospholipids− into vesicles. Here we report the coassembly of human membrane block copolymer vesicle (22). A single attempt by our labora- vesicles with dendrimersomes. The resulting giant hybrid vesicles tory to coassemble bacterial membranes with block copolymers containing human cell membranes, their components, and Janus failed (23). dendrimers are stable for at least 1 y. To demonstrate the utility of Dendrimersomes (DSs) (10, 11) and glycodendrimersomes cell-like hybrid vesicles, hybrids from dendrimersomes and bacte- (GDSs) (24) self-assembled from monodisperse, amphiphilic rial membrane vesicles containing YadA, a bacterial adhesin pro- JDs and Janus glycodendrimers were recently advanced as tein, were prepared. The latter cell-like hybrids were recognized models of biological membranes with tunable size (25), structural by human cells, allowing for adhesion and entry of the hybrid organization (26, 27), and functional surfaces (28). DSs and bacterial vesicles into human cells in vitro. GDSs allow for the design of specific interactions, such as glycan− lectin binding, to be investigated without interference from mammalian cell | bacterial membrane | hybrid vesicles | coassembly | other functional groups present on the biological membrane bacterial adhesin (29). DSs and GDSs exhibit bilayer thicknesses similar to that of liposomes (∼4 nm) assembled from phospholipids (8, 9) and he membranes of human cells are mechanically fragile and excellent stability in buffer at room temperature for several years Tchemically unstable in vitro (1). Therefore, the investigation (10). In comparison, phospholipid-based liposomes or stealth of the functions of biological membranes outside the in vivo natural cellular environment represents a significant challenge. Significance Liposomes assembled from naturally occurring phospholipids (2) and their chemically modified versions (3, 4) are also unsta- Gram-negative bacterial cells such as Escherichia coli contain a ble. Exceptions are stealth liposomes (5, 6), which are vesicles relatively rigid outer membrane, and cross-linked peptidogly- coassembled from phospholipids and water-soluble polymers can in their periplasm, giving them the rigidity and stability to conjugated to phospholipids. The first series of vesicles assem- survive independently in harsh environments. To dismantle bled from synthetic lipids (7, 8) did not solve this stability these strong bacterial cell envelopes, enzymatic processes need problem. Amphiphilic block copolymers (9) were the first am- to be used. In contrast, human cell membranes are much more phiphiles that assembled in stable vesicles named polymersomes. fragile, making it possible to dismantle them more easily by However, block copolymers are not always biocompatible, and relatively mild mechanical disruption. Once these membranes the thickness of the polymersome bilayers is larger than that of are dismantled, they can be coassembled with synthetic liposomes and of natural biological membranes. Amphiphilic phospholipid mimics, named Janus dendrimers, into cell-like Janus dendrimers (JDs) (10, 11) self-assemble into stable and hybrids. This method stabilizes the delicate human cell mem- monodisperse vesicles with bilayer thickness similar to that of branes, introducing the potential for the study of human cell liposomes (12). Since JDs are prepared from naturally occurring membranes and of their constituents in vitro in a more robust phenolic acids (13), they are also biocompatible (10, 11). environment. Phospholipids and amphiphilic block copolymers can be self- Author contributions: S.S.Y., Q.X., M.L.K., M.G., and V.P. designed research; S.S.Y., Q.X., assembled into mixed hybrid phospholipid/block copolymer and S.E.S. performed research; S.S.Y., Q.X., M.L.K., M.G., and V.P. analyzed data; and vesicles (14–17). The limited miscibility and the different thick- S.S.Y., Q.X., S.E.S., W.D.H., M.L.K., M.G., and V.P. wrote the paper. nesses of the phospholipids and the hydrophobic part of the Reviewers: L.P., Aix-Marseille Université, CNRS; and D.A.T., NanoSynthons LLC. block copolymers create complex vesicle morphologies, some- The authors declare no conflict of interest. times with dissimilar bilayer membranes produced by phase This open access article is distributed under Creative Commons Attribution-NonCommercial- separation. A positive outcome of the lack of miscibility and NoDerivatives License 4.0 (CC BY-NC-ND). length similarity between phospholipids and hydrophobic parts 1To whom correspondence may be addressed. Email: [email protected], goulian@sas. of the block copolymers is that the phase-separated fragments upenn.edu, or [email protected]. of phospholipid could accommodate transmembrane proteins in Published online December 27, 2018. 744–752 | PNAS | January 15, 2019 | vol. 116 | no. 3 www.pnas.org/cgi/doi/10.1073/pnas.1811307116 Downloaded by guest on October 1, 2021 liposomes are stable under the same conditions for less than Results and Discussion 1 wk, and phospholipids must be stored at −20 °C, while our JDs Coassembly of Giant DSs with Human Membrane Vesicles. Giant DSs can be stored at room temperature. DSs and GDSs were suc- (diameter ∼2 μmto50μm) were prepared, using previously cessfully coassembled into giant hybrid vesicles with the mem- reported methods, by hydration of amphiphilic JD films on brane and the membrane components of Gram-negative Teflon sheets with ultrapure water or PBS (Fig. 1) (10, 23, 32, bacterium Escherichia coli (23). Transmembrane proteins, such 33). Selected JDs containing hydrophobic 3,5-di-dodecyl benzoic as channel proteins, and lipids from E. coli, as well as fluorescent ester minidendrons and hydrophilic 3,4,5-Tris-triethylele glycol labels and glycans from DSs or GDSs, were incorporated by benzoic ester minidendrons were demonstrated to form stable coassembly into these hybrid cell-like vesicles. Therefore, this giant DSs in water or buffer (10, 23, 32, 33). Giant DSs prepared method overcomes the problems associated with incorporating by this method were coassembled with human membrane vesi- – cell components, including phospholipids and transmembrane cles (HMVs) via the dehydration rehydration technique similar proteins, into polymersomes or other synthetic membranes with to that described recently for bacterial membrane vesicles (BMVs) prepared from Gram-negative bacterium E. coli, except mismatched thickness or other biocompatibility issues (30). Al- that the enzymatic degradation by lysosome/EDTA and sonica- though human cell membranes are expected to be amenable to tion of the outer cross-linked membrane of E. coli is not required similar coassembly with synthetic components from DSs or (23, 34). Only weak mechanical disruption such as centrifugation GDSs, they have never been incorporated into synthetic vesicles, is required to prepare HMVs. Eukaryotic membranes, including despite great interest in the elucidation of the functions of hu- human plasma membranes, differ from E. coli membranes in man cells. Indeed, due to the lack of cell walls and cross-linked their composition of phospholipids as well as the lack of lipo- glycans such as peptidoglycan available in bacterial membranes polysaccharides (32). Eukaryotic/mammalian
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