Cell-derived extracellular vesicles and membranes for tissue repair

Abstract

Humans have a limited postinjury regenerative ability. Therefore, cell-derived biomaterials have long been utilized for tissue repair. Cells with multipotent differentiation potential, such as stem cells, have been administered to patients for the treatment of various diseases. Researchers expected that these cells would mediate tissue repair and regeneration through their multipotency. However, increasing evidence has suggested that in most stem cell therapies, the paracrine effect but not cell differentiation or regeneration is the major driving force of tissue repair. Additionally, ethical and safety problems have limited the application of stem cell therapies. Therefore, nonliving cell-derived techniques such as extracellular vesicle (EV) therapy and cell membrane-based therapy to fulfil the unmet demand for tissue repair are important. Nonliving cell-derived biomaterials are safer and more controllable, and their efficacy is easier to enhance through bioengineering approaches. Here, we described the development and evolution from cell therapy to EV therapy and cell membrane-based therapy for tissue repair. Furthermore, the latest advances in nonliving cell-derived therapies empowered by advanced engineering techniques are emphatically reviewed, and their potential and challenges in the future are discussed.

Keywords: Biomaterials; Cell membrane; Cell therapy; Extracellular vesicles; Regenerative medicine; Stem cells.

Fig. 1

Schematic of cell therapy, extracellular vesicle (EV) therapy and cell membrane-based therapy. All three types of biomaterials utilized in these therapies could be native or engineered. The engineering techniques include genetic approaches and chemical approaches, which could be applied before or after the isolation process of EVs and cell membrane

Fig. 2

Engineered stem cell therapy. A Scheme illustrating an example of genetic engineering of stem cells. Bone marrow–derived mesenchymal stem cells (BM-MSCs) were primed by transduction-mediated hepatocyte growth factor–expressing MSCs (HGF-eMSCs) for enhanced efficacy of vascular regeneration and cardiac function restoration in myocardial infarction models. Reproduced from [25]. © The Authors, some rights reserved; exclusive licensee AAAS. B Concept of hydrogels tethering interferon-gamma (IFN-γ) and encapsulating MSCs. Reproduced from [26], copyright 2019, with permission from Elsevier

Fig. 3

Engineered extracellular vesicle (EV) therapy. A Schematic illustration of genetical modification on the surface of dendritic cell-derived EVs with mesenchymal stem cell (MSC)-binding peptide E7. Reproduced from [75], copyright 2020, with permission from Elsevier. B Schematic illustration of iron oxide nanoparticle (IONP)–incorporated EVs extruded from IONP-treated MSCs being guided to the injured spinal cord under exogenous magnetic guidance. Reproduced with permission from [76]. Copyright 2018 American Chemical Society. C Schematic illustration of EVs from MSCs downregulated expression of a natural bone morphogenetic protein antagonist, exerting improved osteogenic ability. Reproduced with permission from [77]. Copyright 2020 American Chemical Society. D Schematic illustration of a coordinated release of small EVs (SEVs) via remotely triggerable hydrogels, which could be cleaved by exposure to blue light at intervals altered on demand. Reproduced with permission from [78]. Copyright 2019 American Chemical Society. SF-MSCs, synovial fluid-derived MSCs; OA, osteoarthritis; hMSC, human MSC; NV, nanovesicle; SEVs, small EVs

Fig. 4

Native cell membrane-based therapy and therapy with genetic or chemical engineering of cell membrane. A Schematic illustration of the size-variable artificial stem cell spheroid (ASSP), combining the paracrine functions of three-dimensional (3D) SSPs and different types of coating membranes. Reproduced from [102]. © The Authors, some rights reserved; exclusive licensee AAAS. B Schematic illustration of promoted targeting capacity achieved under the navigation of an external magnetic field for cell membrane coating γ-Fe2O3 magnetic NPs. Reproduced with permission from [105]. Copyright 2020 American Chemical Society. C Schematic illustration of xenogeneic cartilage tissue graft coated by autologous red blood cell (RBC) membrane of high stability, inducing less inflammatory responses. Reproduced from [106], Copyright 2020, with permission from Elsevier. D Schematic illustration of CXCR4-overexpressing neural stem cell membranes with enhanced efficacy in stroke treatment with poly(lactic‐co‐glycolic) acid nanoparticles (PLGA NPs) loaded with anti‐oedema agents [107]. Reproduced with permission from [105]. Copyright 2019, Wiley. E Schematic illustration of platelet membrane-coated NPs conjugated with TAT and rtPA that could be sequentially functioned after the responsive cleaving of their connecting structure. Reproduced with permission from [108]. Copyright 2019 American Chemical Society. MP, microparticle; CF, cocktail factor; PAMNs, platelet membrane envelope loaded with l-arginine and γ- Fe2O3 magnetic nanoparticles; CM, cell membrane; LhCG, living hyaline cartilage graft; dLhCG, decellularized LhCG; BBB, blood–brain barrier

Fig. 5

Other cell membrane-based therapy. A Schematic illustration of apoptotic bodies membrane coated mesoporous silica nanoparticle (MSN), which could actively target macrophages for inflammation modulation. Reproduced from [144]. © The Authors, some rights reserved; exclusive licensee AAAS. B Schematic illustration of liposome hybrids with platelet membranes for delivery of rapamycin targeting atherosclerosis. Reproduced from [147], copyright 2020, with permission from Elsevier. C Schematic illustration of cell membrane memetic therapy, which incorporated proteins derived from plasma membrane into lipid NPs to achieve both high surface complexity and better manufacture efficacy. Reproduced by permission from Springer [148], copyright 2016, https://doi.org/10.1038/nmat4644. D Schematic illustration of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) fused with monocyte membranes for improved efficacy of endothelial maturation promotion and macrophage subpopulation modulation. Reproduced from [149], copyright 2020, with permission from Elsevier