Original Article
Biomimetic and immunomodulatory therapeutics as an alternative to natural exosomes for vascular and cardiac applications

https://doi.org/10.1016/j.nano.2021.102385Get rights and content

Abstract

Inflammation is a central mechanism in cardiovascular diseases (CVD), where sustained oxidative stress and immune responses contribute to cardiac remodeling and impairment. Exosomes are extracellular vesicles released by cells to communicate with their surroundings and to modulate the tissue microenvironment. Recent evidence indicates their potential as cell-free immunomodulatory therapeutics for CVD, preventing cell death and fibrosis while inducing wound healing and angiogenesis. Biomimetic exosomes are semi-synthetic particles engineered using essential moieties present in natural exosomes (lipids, RNA, proteins) to reproduce their therapeutic effects while improving on scalability and standardization due to the ample range of moieties available to produce them. In this review, we provide an up-to-date description of the use of exosomes for CVD and offer our vision on the areas of opportunity for the development of biomimetic strategies. We also discuss the current limitations to overcome in the process towards their translation into clinic.

Graphical Abstract

Biomimetic exosomes offer a promising alternative to natural exosomes for the treatment of cardiovascular diseases by reproducing their effects inducing homeostasis, angiogenesis, immunomodulation and preventing fibrosis, while improving their translational potential. Biomimetic exosomes can be engineered from natural exosomes and proteolipidic vesicles. This approach improves the scalability and standardization of the synthesis of biomimetic exosomes following the identification of the essential moieties required to enhance their therapeutic effectiveness. In addition, they offer advantages over the use of proteolipidic vesicles and natural exosomes including the specific targeted distribution, structural cargo stability, reduced immunogenicity and production costs, which should facilitate their translation into clinical-grade therapeutics for the treatment of cardiovascular diseases.

Unlabelled Image
  1. Download : Download high-res image (570KB)
  2. Download : Download full-size image

Section snippets

Inflammation in the cardiovascular system

Inflammation is a common pathophysiological endpoint in CVD, often arising from ischemic conditions. Within the ischemic cardiac milieu, the release of bioactive factors from injured and necrotic cells, such as cytokines and damage-associated molecules, creates a pro-inflammatory environment that attracts circulating leukocytes (namely neutrophils, monocytes and lymphocytes) to the heart. These cells promote an inflammatory storm through the release of antigen-specific cellular immunity and

The role of exosomes in the cardiovascular system

Exosomes are a physiological vehicle for the transmission of signals between cells in the cardiovascular system. They regulate many biological processes involved in tissue homeostasis including cell survival, metabolism, and contraction, while also protecting against conditions such as ischemia and oxidative stress (summarized in Table 1). In this section, we discuss the roles ascribed to the exosomes secreted by cell types that are currently under examination for their contribution to

The need of exosome mimetics

As we have reviewed so far, natural exosomes are a promising avenue to leverage the therapeutic benefits of cardiac and stem cells in CVD. However, exploiting the full potential of natural exosomes requires addressing their limitations. One of the main issues in the use of exosomes for therapeutic applications lies in the number of exosomes that can be retrieved from cell cultures, which would be insufficient to meet the concentrations required for their clinical translation. On a similar note,

Synthesis of biomimetic therapeutics

Biomimetic exosomes, also referred to as exosome mimetics, are engineered delivery platforms resembling natural exosomes in terms of size, physicochemical properties and their protein moieties (including recognized surface canonical markers: tetraspanins (CD9, CD63, CD81), ALG-2-interacting protein X (ALIX) and tumor susceptibility gene 101 (Tsg101)) and molecular cargo.104 These engineered exosomes are attractive alternatives to overcome the limitations faced with natural exosomes and

Biomimetic strategies as therapeutic approaches for the treatment of CVD

To date, biomimetic exosomes for CVD applications are still a developing field, with very few publications available. This should increase over time given the increasing knowledge on the contribution of natural exosomes in CVD, both in health and in disease. Here we discuss the two direct cardiovascular applications of biomimetic exosomes recently published, and we also present the case of some rheumatic and neurovascular diseases that relate to cardiovascular health. The first example of

Solving synthesis and scalability issues with biomimetic exosomes

From our discussion throughout this review, it is clear that exosomes exist in highly heterogeneous presentations and that they can be tailored by manipulating parental cells or by engineering their features to achieve specific tasks. However, challenges in the production process of bioengineered exosomes still exist and stem from issues with their physicochemical characterization, and the standardization of their synthesis protocols. Proper characterization of every exosome construct is

Conclusions

The field of exosomes and exosome mimetics is steadily growing with new insights into their fabrication, as well as into the mechanisms of their effects on biological processes. CVD can benefit from exosome therapeutics due to the wide range of beneficial effects that they may have on cardiac physiology and disease. Given that inflammation is one of the central pathophysiological mechanisms driving CVD, the anti-inflammatory potential of exosome therapies will continue to be studied. Biomimetic

Declaration of competing interest

The authors do not declare any conflict of interest.

Credit author statement

Ramiro A. Villarreal-Leal contributed to the conceptualization and writing of the original manuscript; John P. Cooke contributed to the review/editing of the manuscript; Bruna Corradetti contributed to the conceptualization and review/writing of the manuscript.

References (142)

  • X.H. Sun et al.

    Exosomes of bone-marrow stromal cells inhibit cardiomyocyte apoptosis under ischemic and hypoxic conditions via miR-486-5p targeting the PTEN/PI3K/AKT signaling pathway

    Thromb Res

    (2019)
  • K.M. Luther et al.

    Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells

    J Mol Cell Cardiol

    (2018)
  • J. Kong et al.

    Exosomes of endothelial progenitor cells inhibit neointima formation after carotid artery injury

    J Surg Res

    (2018)
  • J. Hu et al.

    Exosomal Mst1 transfer from cardiac microvascular endothelial cells to cardiomyocytes deteriorates diabetic cardiomyopathy

    Biochim Biophys Acta - Mol Basis Dis

    (2018)
  • Y. Dautova et al.

    Calcium phosphate particles stimulate interleukin-1β release from human vascular smooth muscle cells: a role for spleen tyrosine kinase and exosome release

    J Mol Cell Cardiol

    (2018)
  • C. Wang et al.

    Macrophage-derived mir-155-containing exosomes suppress fibroblast proliferation and promote fibroblast inflammation during cardiac injury

    Mol Ther

    (2017)
  • J.M. Aburto et al.

    Dynamics of life expectancy and life span equality

    Proc Natl Acad Sci U S A

    (2020)
  • Foreman KJ, Marquez N, Dolgert A, Fukutaki K, Fullman N, McGaughey M, et al. Forecasting life expectancy, years of life...
  • J. Ishida et al.

    Springer J

    (2016)
  • S.F. Vatner

    Why so few new cardiovascular drugs translate to the clinics

    Circ Res

    (2016)
  • R. Guo et al.

    Wan F, et al

    (2020)
  • Wagner MJ, Khan M, Mohsin S. Healing the broken heart; the immunomodulatory effects of stem cell therapy. Front Immunol...
  • J.M. Hare et al.

    Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial

    JAMA - J Am Med Assoc

    (2012)
  • K.U. Hong

    Li QH, Guo Y

    (2013)
  • C. Han et al.

    Xu X, et al

    (2016)
  • A. Srivastava et al.

    Exosomes as theranostics for lung cancer

    (2018)
  • M.H. Rashed et al.

    Chavez-Reyes A, et al

    (2017)
  • Hu Q, Su H, Li J, Lyon C, Tang W, Wan M, et al. Clinical applications of exosome membrane proteins. Precis Clin Med...
  • X. Li et al.

    Challenges and opportunities in exosome research—perspectives from biology, engineering, and cancer therapy

    APL Bioeng [Internet]

    (2019 Mar 27)
  • Gallina C, Turinetto V, Giachino C. A new paradigm in cardiac regeneration: the mesenchymal stem cell secretome. Stem...
  • Y.S. Chen et al.

    Exosomes in clinical trial and their production in compliance with good manufacturing practice

    Tzu Chi Medical Journal

    (2020)
  • M.L. Hennrich et al.

    Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline

    Nat Commun

    (2018)
  • R.V. Khatiwala et al.

    Inhibition of p16INK4A to rejuvenate aging human cardiac progenitor cells via the upregulation of anti-oxidant and NFκB signal pathways

    Stem Cell Rev Reports

    (2018)
  • Meyer RA, Sunshine JC, Green JJ. Biomimetic particles as therapeutics. Trends Biotechnol [Internet]. 2015/08/12. 2015...
  • R. Molinaro et al.

    Biomimetic proteolipid vesicles for targeting inflamed tissues

    Nat Mater

    (2016)
  • P. Garg et al.

    Influence of nanotechnology and the role of nanostructures in biomimetic studies and their potential applications

    Biomimetics (Basel, Switzerland) [Internet]

    (2017 May 26)
  • S.D. Prabhu et al.

    The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis

    Circ Res [Internet].

    (2016 Jun 24)
  • Davies JMS, Cillard J, Friguet B, Cadenas E, Cadet J, Cayce R, et al. The oxygen paradox, the French paradox, and...
  • R.J. Vagnozzi et al.

    New myocyte formation in the adult heart: endogenous sources and therapeutic implications

    Circ Res [Internet]

    (2018 Jul 6)
  • J.P. Cooke

    Inflammation and its role in regeneration and repair

    Circ Res

    (2019)
  • J.P. Cooke

    Therapeutic transdifferentiation: a novel approach for vascular disease

    Circ Res

    (2013)
  • N. Sayed et al.

    Jha A, et al

    (2015)
  • S. Meng et al.

    Transdifferentiation requires iNOS activation: role of RING1A S-nitrosylation

    Circ Res

    (2016)
  • P.K. Chanda

    Meng S, Lee J

    (2019)
  • Schaun MI, Eibel B, Kristocheck M, Sausen G, Machado L, Koche A, et al. Cell therapy in ischemic heart disease:...
  • Patil M, Henderson J, Luong H, Annamalai D, Sreejit G, Krishnamurthy P. The art of intercellular wireless...
  • S. Li et al.

    Cardiac progenitor cell-derived exosomes promote H9C2 cell growth via Akt/mTOR activation

    Int J Mol Med

    (2018)
  • L. Barile et al.

    Cardioprotection by cardiac progenitor cell-secreted exosomes: role of pregnancy-associated plasma protein-A

    Cardiovasc Res

    (2018)
  • Ju C, Shen Y, Ma G, Liu Y, Cai J, Kim I man, et al. Transplantation of cardiac mesenchymal stem cell-derived exosomes...
  • J. Xiao et al.

    Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4

    Cell Death Dis

    (2016)

    • Cited by (9)

    View all citing articles on Scopus

    Acknowledgments

    BC acknowledges support through Sêr Cymru II scheme, funded by the European Union's Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement no. 663830, the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF) and Houston Methodist Research Institute. RAV acknowledges CONACYT for his graduate research fellow stipend (859295) at Tecnologico de Monterrey. JPC receives support from the National Institutes of Health (R01HL148338, R01HL133254, R01HL149303, R01GM125632) and the Cancer Prevention Research Institute of Texas (CPRIT RP150611). This work was made possible in part by the generous support of the George And Angelina Kostas Research Center for Cardiovascular Medicine; as well as the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation.

    View full text
    © 2021 Elsevier Inc. All rights reserved.