Biological Nanotherapeutics for Liver Disease

Abstract

Extracellular vesicles (EVs) are a heterogeneous group of biological nano-sized vesicles that are released from cells and contribute to intercellular communication. Emerging knowledge about their biogenesis, composition, release, and uptake has resulted in broad interest in elucidating their potential roles in disease pathophysiology. The distinct biological properties of these biological nanoparticles emphasize several appealing advantages for potential therapeutic applications compared with the use of synthetic nanoparticles. When administered systemically, EVs are taken up and sequestered within the liver, further emphasizing opportunities for therapeutic use. Consequently, there is growing interest in their use for liver diseases. EVs can be used directly as therapeutics, and several studies have highlighted the intrinsic therapeutic properties of mesenchymal stem cell-derived EVs for chronic and acute liver diseases. Alternatively, EVs can be modified to facilitate their use for the delivery of therapeutic cargo. In this review, we discuss the cellular sources of EV, provide a concise overview of their potential use in diverse processes, and outline several promising applications for the use of EV-based therapeutics for liver diseases. The use of EV-based therapeutics provides a viable approach to target hepatic pathophysiology. (Hepatology 2021;74:2863-2875). Extracellular Vesicles as Biological NanotherapeuticsExtracellular vesicles (EVs) are lipid bilayer encapsulated biological nanoparticles that are released from mammalian cells. They can be taken up by and transfer their cargo into nearby cells, thereby contributing to intercellular communication. EVs are also present within body fluids and in blood and can be transported to distant tissues to exert biological effects. There is growing interest in elucidating the biological roles of EVs and their involvement in physiological or disease-relevant processes. There are several different types of EVs, such as exosomes or microvesicles (MVs). These differ in their modes of biogenesis, size, morphology, membrane composition, and cargo profiles. Their biological functions and biophysical properties support the development of EVs as a therapeutic platform for human diseases. Although the therapeutic use of different subtypes of vesicles has been reported, these cannot be readily distinguished due to their concomitant presence within the biological milieu, the overlap of size, composition and cargo, and the lack of subtype-specific markers. Thus, we collectively refer to all subtypes of cell-derived vesicles herein as EVs. In this overview, we outline the promise and potential use of EV-based therapeutics for liver diseases. SoURCeS oF tHeRapeUtIC eVsEVs are ubiquitously expressed by most if not all cell types, and are detectable in the tissue milieu,

Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents

“…In addition, EVs can be surfacemodified or loaded with drugs to further enhance their therapeutic use. 142 Therefore, compared to synthetic nanomaterials, the unique biological characteristics of EVs underscore their potential application advantages in anti-fibrosis therapy, including their inherent stability, good biocompatibility, low immunogenicity, and tendency to accumulate in the liver. 143 As a pathway for intercellular molecular transfer, EVs may drive or inhibit pathogenic pathways in various liver cells, depending on the phenotypes of donor and recipient cells and the nature of the molecular messages transmitted between them.…”

“…In addition, EVs can be surface-modified or loaded with drugs to further enhance their therapeutic use. 142 Therefore, compared to synthetic nanomaterials, the unique biological characteristics of EVs underscore their potential application advantages in anti-fibrosis therapy, including their inherent stability, good biocompatibility, low immunogenicity, and tendency to accumulate in the liver. 143…”

Extracellular Vesicles in Non-alcoholic Fatty Liver Disease and Alcoholic Liver Disease

“…Due to the inherent regenerative capacity of liver tissue and the tropism of systemic injection of nanovesicles in this organ, the liver is an ideal target for EVs based therapy ( Borrelli et al, 2018 ). Currently, EVs based therapy on liver diseases are still in preclinical stage and in most of these studies, EVs are derived from mesenchymal stem cells (MSCs; Driscoll et al, 2021 ). EVs from amnion-derived MSCs may improve inflammation and fibrogenesis in rat models of NASH and liver fibrosis by attenuating the activation of HSC and Kupffer cells ( Ohara et al, 2018 ).…”

Enrichment Methods for Murine Liver Non-Parenchymal Cells Differentially Affect Their Immunophenotype and Responsiveness towards Stimulation

“…Nanodrugs have the potential to co-deliver various agents in a tissue- and even cell type-specific manner, thereby reducing toxicity and other unwanted side effects associated with non-specific uptake of conventional therapeutics [ 37 ]. Therefore, both with regard to nanodrugs designed for the treatment of liver diseases [ 38 ] as well as nano-formulations developed to address other organs and cell types, it is highly important to address potential uptake by the liver.…”