RESUMEN
Gene editing technologies have the potential to correct genetic disorders by modifying, inserting, or deleting specific DNA sequences or genes, paving the way for a new class of genetic therapies. While gene editing tools continue to be improved to increase their precision and efficiency, the limited efficacy of in vivo delivery remains a major hurdle for clinical use. An ideal delivery vehicle should be able to target a sufficient number of diseased cells in a transient time window to maximize on-target editing and mitigate off-target events and immunogenicity. Here, we review major advances in novel delivery platforms based on cell-derived vesicles - extracellular vesicles and virus-like particles - for transient delivery of gene editing payloads. We discuss major findings regarding packaging, in vivo biodistribution, therapeutic efficacy, and safety concerns of cell-derived vesicles delivery of gene editing cargos and their potential for clinical translation.
Asunto(s)
Vesículas Extracelulares , Edición Génica , Técnicas de Transferencia de Gen , Humanos , Edición Génica/métodos , Animales , Vesículas Extracelulares/metabolismo , Terapia Genética/métodosRESUMEN
Nanovesicles and bio-vesicles (BVs) have emerged as promising tools to achieve targeted cancer therapy due to their ability to overcome many of the key challenges currently being faced with conventional chemotherapy. These challenges include the diverse and often complex pathophysiology involving the progression of cancer, as well as the various biological barriers that circumvent therapeutic molecules reaching their target site in optimum concentration. The scientific evidence suggests that surface-functionalized nanovesicles and BVs camouflaged nano-carriers (NCs) both can bypass the established biological barriers and facilitate fourth-generation targeting for the improved regimen of treatment. In this review, we intend to emphasize the role of surface-functionalized nanovesicles and BVs camouflaged NCs through various approaches that lead to an improved internalization to achieve improved and targeted oncotherapy. We have explored various strategies that have been employed to surface-functionalize and biologically modify these vesicles, including the use of biomolecule functionalized target ligands such as peptides, antibodies, and aptamers, as well as the targeting of specific receptors on cancer cells. Further, the utility of BVs, which are made from the membranes of cells such as mesenchymal stem cells (MSCs), white blood cells (WBCs), red blood cells (RBCs), platelets (PLTs) as well as cancer cells also been investigated. Lastly, we have discussed the translational challenges and limitations that these NCs can encounter and still need to be overcome in order to fully realize the potential of nanovesicles and BVs for targeted cancer therapy. The fundamental challenges that currently prevent successful cancer therapy and the necessity of novel delivery systems are in the offing.
Asunto(s)
Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Ligandos , Péptidos/uso terapéuticoRESUMEN
Isothiocyanates (ITCs) have low stability in aqueous conditions, reducing their bioavailability when used as food ingredients. Therefore, the aim of this work was to increase the stability of the ITCs present in extracts of Bimi® edible parts by nanoencapsulation using cauliflower-derived plasma membrane vesicles. The bioactivity of these nanoencapsulates was evaluated in a HepG2 hepatocyte cell line in a model for low-grade chronic inflammation. The vesicles showed a higher capacity of retention in the in vitro gastrointestinal digestion for 3,3-diindolylmethane (DIM), indole-3-carbinol (I3C) and sulforaphane (SFN). Furthermore, Transmission Electron Microscopy (TEM) analysis of the vesicles revealed a decreased size under acidic pH and a release of their cargo after the intestinal digestion. The HepG2 experiments revealed differences in metabolism under the condition of chronic inflammation. The cauliflower-derived plasma membrane vesicles are able to enhance the stability of ITCs through the in vitro gastrointestinal digestion, improving their bioaccesibility and potential bioavailability.
Asunto(s)
Brassica , Isotiocianatos , Digestión , Células Hep G2 , Humanos , Inflamación , Extractos Vegetales/farmacologíaRESUMEN
Gap junction (GJ) channels facilitate cell-cell communication through the exchange of chemical and mechanical signals, ensuring proper tissue development and homeostasis. The complex, disease stage-dependent role of connexins in breast cancer progression has been extensively studied over the past two decades. In the early stages of breast cancer, substantial evidence supports the role of GJ channels, formed by connexins at the interfaces between neighbouring cells, as suppressors of cell migration and proliferation. These findings suggest that materials that reintroduce connexins into the tumour cell environment have the potential to inhibit cell migration. Here, we report that exposure of highly metastatic MDA-MB-231 breast tumour cells to connexin-rich biovesicle materials potently suppresses cell migration. Specifically, these biovesicles, which can form GJ interfaces with cells, were extracted from the plasma membrane of donor cells engineered to express a high concentration of functional connexin 43 channels. These connexin-rich membrane materials dramatically reduced cell migration in both a transwell migration assay and a scratch closure assay. Collectively, these results suggest that using membrane materials to reintroduce connexins into the tumour cell environment provides a novel approach for combating cell migration and invasion.