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WIREs Nanomed Nanobiotechnol
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Oral nucleic acid therapy using multicompartmental delivery systems

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Nucleic acid‐based therapeutics has the potential for treating numerous diseases by correcting abnormal expression of specific genes. Lack of safe and efficacious delivery strategies poses a major obstacle limiting clinical advancement of nucleic acid therapeutics. Oral route of drug administration has greater delivery challenges, because the administered genes or oligonucleotides have to bypass degrading environment of the gastrointestinal (GI) tract in addition to overcoming other cellular barriers preventing nucleic acid delivery. For efficient oral nucleic acid delivery, vector should be such that it can protect encapsulated material during transit through the GI tract, facilitate efficient uptake and intracellular trafficking at desired target sites, along with being safe and well tolerated. In this review, we have discussed multicompartmental systems for overcoming extracellular and intracellular barriers to oral delivery of nucleic acids. A nanoparticles‐in‐microsphere oral system‐based multicompartmental system was developed and tested for in vivo gene and small interfering RNA delivery for treating colitis in mice. This system has shown efficient transgene expression or gene silencing when delivered orally along with favorable downstream anti‐inflammatory effects, when tested in a mouse model of intestinal bowel disease. WIREs Nanomed Nanobiotechnol 2018, 10:e1478. doi: 10.1002/wnan.1478 This article is categorized under: Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies
Barriers to oral nucleic acid delivery. Opportunities and challenges in oral delivery of nanoparticles using microscale carriers. (a) Aggregated particles (i.e., with blood components or carrier matrix molecules) leading to restricted release; (b) physical docking and/or accumulation on cell surface; (c) microparticle internalization into the cell followed by endosomal release; (d) nanoparticles within the microscale device or (e) the microparticle itself; (f) particle uptake into the nucleus; (g) crossing of the particles into the bloodstream; and (h) particles that are contaminated with the microscale carrier matrix, interfering with further delivery. (Reprinted with permission from Ref . Copyright 2012 Elsevier)
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Tumor necrosis factor‐α (TNF‐α) and cyclin‐D1 silencing with nanoparticles‐in‐microsphere oral system (NiMOS) in inflammatory bowel disease (IBD). mRNA and protein expression profiles in control and small interfering RNA (siRNA)‐treated mice. (Reprinted with permission from Ref . Copyright 2011 The American College of Gastroenterology)
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Interleukin‐10 (IL‐10) expression and therapeutic effects in inflammatory bowel disease (IBD). Murine IL‐10 transgene expression (a) and reduction in the levels of proinflammatory cytokines tumor necrosis factor‐α (TNF‐α) (b) and IL‐1β (c) upon delivery of murine IL‐10‐expressing plasmid DNA administered in nanoparticles‐in‐microsphere oral system (NiMOS). (d) The therapeutic benefits of oral IL‐10 gene therapy as determined by tissue histology upon oral administration of murine IL‐10‐expressing plasmid DNA in NiMOS. (Reprinted with permission from Ref . Copyright 2008 Macmillan Publishers Limited)
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Distribution of nanoparticles‐in‐microsphere oral system (NiMOS) particles after oral administration. Gastrointestinal distribution following oral administration of 111In‐labeled gelatin nanoparticles and 111In‐labeled gelatin nanoparticles encapsulated in the NiMOS in 24‐h fasted female Balb/C mice (a and b) or Wistar rats (c). (Reprinted with permission from Ref . Copyright 2012 Elsevier)
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Schematic illustration showing the cross‐sectional view of nanoparticles‐in‐microsphere oral system (NiMOS). On the left is the scanning electron microscopy (SEM) image of gelatin nanoparticles, which are <200 nm in diameter, and can physically encapsulate plasmid DNA at a loading efficiency of >93%. On the right is the SEM image of 2–5 mm NiMOS with the overall DNA encapsulation efficiency of ~46%. (Reprinted with permission from Ref . Copyright 2008 Macmillan Publishers Limited)
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RNA interference therapy to silence the DMT1 expression. (a) Nonheme iron from diet is reduced to ferrous iron (Fe2+) by the duodenal cytochrome b (Dcytb) and absorbed by the divalent metal transporter 1 (DMT1). Iron can either be stored in the cell by binding to ferritin or released into blood through ferroportin (FPN). Fe2+ is then oxidized by hephaestin and binds to transferrin (Tf) for circulation. DMT1 siRNA in NiMOS given orally will promote degradation of DMT1 mRNA in the enterocyte and downregulate DMT1 expression. As a result, intestinal uptake of nonheme iron from diet will be attenuated. (b) Tf‐bound iron in blood is first transported into the endosome of the erythropoietic tissues by the transferrin receptor 1 (TfR) and then reduced by Steap3. The resultant Fe2+ is transported by endosomal DMT1 to mitochondria for heme synthesis. DMT1 siRNA in NiMOS will not affect the transcription of DMT1 in the reticulocyte as the complex is not absorbed and unavailable in the circulation.
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Iron homeostasis and disorders. Normal: ① Dietary iron enters plasma. ② Most iron (75%) is transferred to the bone marrow ③ for red blood cell (RBC) production. ④ RBCs circulate for 120 days and are digested by macrophages. ⑤ Iron is released back to plasma and recycled for ② another round of RBC production. ⑥ The rest of iron (25%) is taken up by organs for physiological function, stored in the liver, or excreted by urine or bile secretion. Iron overload: ⑦ When excess iron enters due to genetic disorders (hemochromatosis) or ⑧ blood transfusion (thalassemia, sickle cell anemia), ⑨ iron is accumulated in the liver and heart and exerts toxic effects. ⑨ Brain iron levels also increase with age or by prolonged exposures to high iron. Chelation therapy: ⑩ Chelators increase iron excretion, but display serious side effects.
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Schematic representation of multicompartmental gene delivery systems. (Reprinted with permission from Ref . Copyright 2012 Elsevier)
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Intestinal tissue histology before and after treatment. Microscopic evaluation of colonic tissue histopathology. Bright‐field images of hematoxylin and eosin‐stained sections of the colon harvested from each control and test group. Images are shown at magnifications of ×10 and ×40 from tissue cryosections obtained on day 10 and day 12 of the study. Sections from the first control group show normal and healthy colon tissue. Intestinal tissues from the dextran sulfate sodium (DSS) control group, the group treated with blank and scrambled small interfering RNA (siRNA) nanoparticles‐in‐microsphere oral system (NiMOS) showed a severe infiltration of white blood cells, abnormal mucosal structure, and a certain degree of goblet cell depletion. Tissue from the group receiving tumor necrosis factor‐α (TNF‐α), cyclin D1 (CyD1), or combined TNF/CyD1 silencing NiMOS showed signs of regeneration and exhibited a tissue architecture more closely resembling that of healthy tissue in the normal control group. Occurrence of goblet cells is indicated by red arrows; cell infiltration and abnormal tissue histology is indicated by black arrows. (Reprinted with permission from Ref . Copyright 2011 The American College of Gastroenterology)
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