Bioengineering Extracellular Vesicles for the Treatment of Cardiovascular Diseases

Abstract

contributing factors of these diseases are numerous, including genetics, diet, smoking, and lack of exercise. [1][2][3] With development of angiography, drug-eluting stents, balloon catheters, bypass surgery, and new disease-modifying drug therapies, there has been significant improvement in the care and treatment of patients with CVD. [4] Despite these innovations and progress, CVD is still the leading cause of death in the US and worldwide. Furthermore, these treatment options bring their own set of complications, including intimal hyperplasia and thrombosis, as well as drug therapy side effects. Therefore, broader therapeutic interventions are still needed in order to ameliorate the devastating impacts of CVD. Recently, a new class of therapeutics has emerged that is known as extracellular vesicles (EVs). EVs are membranebound vesicles released by different types of prokaryotic and eukaryotic cells, and are ubiquitously found in most body fluids such as blood, urine, breast milk, saliva, and cerebrospinal fluid. [5] In general, EVs can be classified into three subclasses which are differentiated by their biogenesis mechanisms. [5,6] The first class of EVs is microvesicles, also known as ectosomes or microparticles. They are produced by the outward budding and fission of the plasma membrane and range from 50 nm to 1 micron in size. [7,8] The second EV subset are termed apoptotic bodies (50 nm to 5 microns) and are released when plasma membrane blebbing occurs during late apoptosis. The final EV subset is known as exosomes. Exosomes are the smallest type of EV (also often referred to as sEV), ranging between 50-150 nm, and originate from the inward budding of multivesicular bodies (MVB). Exosomes are released into the extracellular space upon fusion of MVBs with the plasma membrane, specifically at the lipid raft subdomains. [9,10] All subsets of vesicles contain bioactive cargo, including proteins, mRNAs, microRNAs (miRNAs, miRs), and lipids, that are efficiently delivered to recipient cells to regulate different biological processes. [6,8,[11][12][13] Within the cardiovascular system, EVs play important roles in maintaining normal physiological function by facilitating cellular crosstalk. [8,11,14] Under disease or injury conditions, EV phenotypes are seen to shift in order to indicate cardiovascular dysfunction and to restore physiological balance. However, administration of EVs as therapeutics has been limited due to difficulties in isolation and standardization, ineffective targeting, and poor retention. [15,16] Advances in research and technology have addressed these challenges by engineering EVs to augment Cardiovascular diseases (CVD) remain one of the leading causes of mortality worldwide. Despite recent advances in diagnosis and interventions, there is still a crucial need for new multifaceted therapeutics that can address the complicated pathophysiological mechanisms driving CVD. Extracellular vesicles (EVs) are nanovesicles that are secreted by all types of cells to transport molecular cargo and regu...

The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy

“…Depending on donor cells and their activation status, EVs can promote cardiomyocyte survival, regulate hypertrophy and autophagy, reduce fibrosis and increase angiogenesis to reduce infarct size, and preserve cardiac functions. 1,130 Moreover, EVs from differentiating cardiomyocytes reportedly reprogram resident fibroblasts toward cardiomyocytes with excellent efficiency, 142 which can be therapeutically harnessed for replacing lost cardiomyocytes.…”

“…Since the first report in 2010, there are plethora of studies highlighting the use of EVs as potential cell-free therapeutics for CVD pathologies, such as MI, limb ischemia, atherosclerosis, and stroke. 1,130 EVs isolated from multiple cell types (grown as 2-dimensional cultures or as 3-dimensional cultures 131 ) have been shown to package cardiac therapeutic cargo (including proteins, 132,133 miRs, 85,134,135 long noncoding RNA 136 ), which provides cardio–protective functions in preclinical mice, 132,133,137 rat, 138,139 and pig 127 models (via intramyocardial 127,140,141 or intracoronary 129,138 administration) of CVDs. Depending on donor cells and their activation status, EVs can promote cardiomyocyte survival, regulate hypertrophy and autophagy, reduce fibrosis and increase angiogenesis to reduce infarct size, and preserve cardiac functions.…”

Tuning the Extracellular Vesicles Membrane through Fusion for Biomedical Applications

“…The desired content can be encapsulated by smoothly fusing the synthetic lipid vesicles with the lipid components of the exosome membrane [ 99 ]. This fusion can be facilitated by several different approaches, such as chemically triggered, freeze–thaw cycles, and extrusion methods [ 50 , 100 , 101 , 102 , 103 , 104 , 105 ].…”

Prospective applications of extracellular vesicle-based therapies in regenerative medicine: implications for the use of dental stem cell-derived extracellular vesicles

“…EVs have risen as a compelling prospect for cell-free therapeutic schemes to promote tissue regeneration. This is attributed to their remarkable advantages, encompassing superior biosafety, the capacity to traverse biological barriers, and the ability to protect their contents from being degraded ( Lazar et al, 2021 ; Ramasubramanian et al, 2022 ). Furthermore, owing to their powerful regenerative capacity and easy accessibility, the demand for stem cell-derived EVs is increasing in regenerative medicine ( He et al, 2018 ; Liao et al, 2019 ; Liu and Su, 2019 ; Xiao et al, 2019 ).…”