title: Extracellular vesicle-mediated delivery of molecular compounds into gametes and embryos: learning from nature.
abstract: BACKGROUND
  Currently, even the most sophisticated methods of assisted reproductive technology (ART) allow us to achieve live births in only approximately 30% of patients, indicating that our understanding of the fine mechanisms underlying reproduction is far from ideal. One of the main challenges associated with studies of gamete structure and function is that these cells are remarkably resistant towards the uptake of exogenous substances, including 'molecular research tools' such as drugs, biomolecules and intracellular markers. This phenomenon can affect not only the performance of reproductive biology research techniques, but also the outcomes of the in vitro handling of gametes, which forms the cornerstone of ART. Improvement of intra-gamete delivery in a non-aggressive fashion is vital for the investigation of gamete physiology, and the advancement of infertility treatment. In this review, we outline the current state of nanomaterial-mediated delivery into gametes and embryos in vitro, and discuss the potential of a novel exciting drug delivery technology, based upon the use of targeted 'natural' nanoparticles known as extracellular vesicles (EVs), for reproductive science and ART, given the promising emerging data from other fields.
  
  
  METHODS
  A comprehensive electronic search of PubMed and Web of Science databases was performed using the following keywords: 'nanoparticles', 'nanomaterials', 'cell-penetrating peptides', 'sperm', 'oocyte', 'egg', 'embryo', 'exosomes', 'microvesicles', 'extracellular vesicles', 'delivery', 'reproduction', to identify the relevant research and review articles, published in English up to January 2015. The reference lists of identified publication were then scanned to extract additional relevant publications.
  
  
  RESULTS
  Biocompatible engineered nanomaterials with high loading capacity, stability and selective affinity represent a potential versatile tool for the minimally invasive internalization of molecular cargo into gametes and embryos. However, it is becoming increasingly clear that the translation of these experimental tools into clinical applications is likely to be limited by their non-biodegradable nature. To allow the subsequent use of these methodologies for clinical ART, studies should utilize biodegradable delivery platforms, which mimic natural mechanisms of molecular cargo trafficking as closely as possible. Currently, EVs represent the most physiological intracellular delivery tools for reproductive science and medicine. These natural mediators of cell communication combine the benefits of engineered nanomaterials, such as the potential for in vitro production, targeting and loading, with the essential feature of biodegradability.
  
  
  CONCLUSIONS
  We anticipate that future investigations into the possibility of applying EVs for the intentional intracellular delivery of molecular compounds into gametes and embryos will open new horizons for reproductive science and clinical ART, ultimately leading to improvements in patient care.
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Level 3, Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Barkalina
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Level 3, Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
authors.forename: Celine
authors.initials: C
authors.lastname: Jones
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Le Gros Clark Building, South Parks Road, Oxford OX1 3QX, UK.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Level 3, Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK kevin.coward@obs-gyn.ox.ac.uk.
authors.forename: Kevin
authors.initials: K
authors.lastname: Coward
mesh_terms: D002450:Cell Communication / Q000502:physiology*; D057846:Cell-Penetrating Peptides / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D004622:Embryo, Mammalian / Q000502:physiology*; D000067128:Extracellular Vesicles / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D053758:Nanoparticles; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D011247:Pregnancy; D027724:Reproductive Techniques, Assisted; D013094:Spermatozoa / Q000166:cytology / Q000502:physiology
chemical_list: D057846:Cell-Penetrating Peptides
keywords: assisted reproductive technology; delivery; extracellular vesicles; gametes; nanomaterials