Cell-Derived Vesicles for in Vitro and in Vivo Targeted Therapeutic Delivery.
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ABSTRACT:
SUBMITTER: Snell AA
PROVIDER: S-EPMC6681979 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cell membranes have recently emerged as a new source of materials for molecular delivery systems. Cell membranes have been extruded or sonicated to make nanoscale vesicles. Unlike synthetic lipid or polymeric nanoparticles, cell membrane-derived vesicles have a unique multicomponent feature, comprising lipids, proteins, and carbohydrates. Because cell membrane-derived vesicles contain the intrinsic functionalities and signaling networks of their parent cells, they can overcome various obstacles encountered in vivo. Moreover, the different natural combinations of membranes from various cell sources expand the range of cell membrane-derived vesicles, creating an entirely new category of drug-delivery systems. Cell membrane-derived vesicles can carry therapeutic agents within their interior or can coat the surfaces of drug-loaded core nanoparticles. Cell membranes typically come from single cell sources, including red blood cells, platelets, immune cells, stem cells, and cancer cells. However, recent studies have reported hybrid sources from two different types of cells. This review will summarize approaches for manufacturing cell membrane-derived vesicles and treatment applications of various types of cell membrane-derived drug-delivery systems, and discuss challenges and future directions.
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Project description:Natural extracellular vesicles (EVs) are ideal drug carriers due to their remarkable biocompatibility. Their delivery specificity can be achieved by the conjugation of targeting ligands. However, existing methods to engineer target-specific EVs are tedious or inefficient, having to compromise between harsh chemical treatments and transient interactions. Here, we describe a novel method for the covalent conjugation of EVs with high copy numbers of targeting moieties using protein ligases. Conjugation of EVs with either an epidermal growth factor receptor (EGFR)-targeting peptide or anti-EGFR nanobody facilitates their accumulation in EGFR-positive cancer cells, both in vitro and in vivo. Systemic delivery of paclitaxel by EGFR-targeting EVs at a low dose significantly increases drug efficacy in a xenografted mouse model of EGFR-positive lung cancer. The method is also applicable to the conjugation of EVs with peptides and nanobodies targeting other receptors, such as HER2 and SIRP alpha, and the conjugated EVs can deliver RNA in addition to small molecules, supporting the versatile application of EVs in cancer therapies. This simple, yet efficient and versatile method for the stable surface modification of EVs bypasses the need for genetic and chemical modifications, thus facilitating safe and specific delivery of therapeutic payloads to target cells.
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Project description:Mesenchymal stem cells (MSCs) are multipotent cells with regenerative and immunomodulatory properties. Several aspects of MSC function have been attributed to the paracrine effects of MSC derived extracellular vesicles (EVs). Although MSC EVs show great promise for regenerative medicine applications, insights into their uptake mechanisms by different target cells and the ability to control MSC EV properties for defined function in vivo have remained elusive knowledge gaps. The primary goal of this study is to elucidate how the basic properties of MSC derived EVs can be exploited for function-specific activity in regenerative medicine. Our first important observation is that, MSC EVs possess a common mechanism of endocytosis across multiple cell types. Second, altering the MSC state by inducing differentiation into multiple lineages did not affect the exosomal properties or endocytosis but triggered the expression of lineage-specific genes and proteins in vitro and in vivo respectively. Overall, the results presented in this study show a common mechanism of endocytosis for MSC EVs across different cell types and the feasibility to generate functionally enhanced EVs by modifications to parental MSCs.
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2022-10-19 | GSE206164 | GEO
Project description:As an element of the cellular signaling systems, extracellular vesicles (EVs) exhibit many desirable traits for usage as targeted delivery vehicles. When administered, EVs cause little to no toxic or immune response, stay in circulation for longer periods compared to synthetic carriers, preferentially accumulate in tissues that are the same or similar to their cell-of-origin and can pass through the blood-brain barrier. Combined, these traits make neural EVs a particularly promising tool for delivering drugs to the brain. This study aims to combine tissue and EVs engineering to prepare neural differentiated cells derived EVs that exhibit neural properties, to develop an effective, tissue-homing drug and gene delivery platform for the brain. Early neural differentiated cell-derived EVs were produced with neural characteristics from neural differentiated human neonatal dermal fibroblasts. The EVs carried key neural proteins such as Nestin, Sox2 and Doublecortin. The cellular uptake of early neural differentiated cell-derived EVs was higher compared to non-neural EVs during in vitro uptake assays on neuroblastoma cells. Moreover, eND-EVs were significantly decreased the viability of neuroblastoma cells. In conclusion, this study revealed that early neural differentiated cell-derived EVs have potential as a promising drug carrier for the treatment of various neural disorders.
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Project description:The advent of novel therapeutics in recent years has urged the need for a safe, non-immunogenic drug delivery vector capable of delivering therapeutic payloads specifically to diseased cells, thereby increasing therapeutic efficacy and reducing side effects. Extracellular vesicles (EVs) have garnered attention in recent years as a potentially ideal vector for drug delivery, taking into account their intrinsic ability to transfer bioactive cargo to recipient cells and their biocompatible nature. However, natural EVs are limited in their therapeutic potential and many challenges need to be overcome before engineered EVs satisfy the levels of efficiency, stability, safety and biocompatibility required for therapeutic use. Here, we demonstrate that an enzyme-mediated surface functionalization method in combination with streptavidin-mediated conjugation results in efficient surface functionalization of EVs. Surface functionalization using the above methods permits the stable and biocompatible conjugation of peptides, single domain antibodies and monoclonal antibodies at high copy number on the EV surface. Functionalized EVs demonstrated increased accumulation in target cells expressing common cancer associated markers such as CXCR4, EGFR and EpCAM both in vitro and in vivo. The functionality of this approach was further highlighted by the ability of targeting EVs to specifically deliver therapeutic antisense oligonucleotides to a metastatic breast tumor model, resulting in increased knockdown of a targeted oncogenic microRNA and improved metastasis suppression. The method was also used to equip EVs with a bifunctional peptide that targets EVs to leukemia cells and induces apoptosis, leading to leukemia suppression. Moreover, we conducted extensive testing to verify the biocompatibility, and safety of engineered EVs for therapeutic use, suggesting that surface modified EVs can be used for repeated dose treatment with no detectable adverse effects. This modular, biocompatible method of EV engineering offers a promising avenue for the targeted delivery of a range of therapeutics while addressing some of the safety concerns associated with EV-based drug delivery.
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Project description:Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about in vivo EVs trafficking upon delivery is required before effective clinical translation. Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC-derived EVs for tissue regeneration, we review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs.
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Project description:Extracellular vesicles (EVs) are cell-derived membrane-bound nanoparticles, which act as shuttles, delivering a range of biomolecules to diverse target cells. They play an important role in maintenance of biophysiological homeostasis and cellular, physiological, and pathological processes. EVs have significant diagnostic and therapeutic potentials and have been studied both in vitro and in vivo in many fields. Mesenchymal stem cells (MSCs) are multipotent cells with many therapeutic applications and have also gained much attention as prolific producers of EVs. MSC-derived EVs are being explored as a therapeutic alternative to MSCs since they may have similar therapeutic effects but are cell-free. They have applications in regenerative medicine and tissue engineering and, most importantly, confer several advantages over cells such as lower immunogenicity, capacity to cross biological barriers, and less safety concerns. In this review, we introduce the biogenesis of EVs, including exosomes and microvesicles. We then turn more specifically to investigations of MSC-derived EVs. We highlight the great therapeutic potential of MSC-derived EVs and applications in regenerative medicine and tissue engineering.
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