An Orthogonal Array Optimization of Lipid-like Nanoparticles for mRNA Delivery in Vivo.

Systemic delivery of mRNA-based therapeutics remains a challenging issue for preclinical and clinical studies. Here, we describe new lipid-like nanoparticles (TT-LLNs) developed through an orthogonal array design, which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350-fold with significantly reduced experimental workload. One optimized TT3 LLN, termed O-TT3 LLNs, was able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA based nanomaterials merit further development for therapeutic applications.

[1]  D. Heller,et al.  Lipid‐Modified Aminoglycoside Derivatives for In Vivo siRNA Delivery , 2013, Advanced materials.

[2]  K. Leong,et al.  Transfection efficiency and transgene expression kinetics of mRNA delivered in naked and nanoparticle format. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[3]  Yong Huang,et al.  Promoterless gene targeting without nucleases ameliorates haemophilia B in mice , 2014, Nature.

[4]  Robert Langer,et al.  Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates , 2014, Proceedings of the National Academy of Sciences.

[5]  Yuhua Wang,et al.  Systemic delivery of modified mRNA encoding herpes simplex virus 1 thymidine kinase for targeted cancer gene therapy. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[6]  Ron Weiss,et al.  Synthetic biology devices and circuits for RNA-based ‘smart vaccines’: a propositional review , 2015, Expert review of vaccines.

[7]  James D Bryers,et al.  Multifunctional triblock copolymers for intracellular messenger RNA delivery. , 2012, Biomaterials.

[8]  Gaurav Sahay,et al.  Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. , 2012, Journal of the American Chemical Society.

[9]  R. Choi,et al.  Chemical and biological assessment of Angelicae Sinensis Radix after processing with wine: an orthogonal array design to reveal the optimized conditions. , 2011, Journal of agricultural and food chemistry.

[10]  Robert Langer,et al.  A combinatorial library of lipid-like materials for delivery of RNAi therapeutics , 2008, Nature Biotechnology.

[11]  Shaobing Zhou,et al.  Investigation on process parameters of electrospinning system through orthogonal experimental design , 2007 .

[12]  Yuepu Pu,et al.  Optimal activation of carboxyl-superparamagnetic iron oxide nanoparticles bioconjugated with antibody using orthogonal array design. , 2013, Journal of nanoscience and nanotechnology.

[13]  Thomas Krucker,et al.  Nonviral delivery of self-amplifying RNA vaccines , 2012, Proceedings of the National Academy of Sciences.

[14]  Kathryn A. Whitehead,et al.  Lipid-like materials for low-dose, in vivo gene silencing , 2010, Proceedings of the National Academy of Sciences.

[15]  R. Herzog,et al.  Animal models of hemophilia. , 2012, Progress in molecular biology and translational science.

[16]  Mark E. Davis,et al.  PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. , 2004, European journal of cell biology.

[17]  K. Leong,et al.  Messenger RNA (mRNA) nanoparticle tumour vaccination. , 2014, Nanoscale.

[18]  Benjamin C. Tang,et al.  Lipid‐Like Nanomaterials for Simultaneous Gene Expression and Silencing In Vivo , 2014, Advanced healthcare materials.

[19]  F. Rosendaal,et al.  High levels of factor IX increase the risk of venous thrombosis. , 2000, Blood.

[20]  S. Pascolo.  Vaccination with messenger RNA (mRNA). , 2008, Handbook of experimental pharmacology.

[21]  D. Irvine,et al.  In vitro and in vivo mRNA delivery using lipid-enveloped pH-responsive polymer nanoparticles. , 2011, Molecular pharmaceutics.

[22]  Shubiao Zhang,et al.  Toxicity of cationic lipids and cationic polymers in gene delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[23]  P. Monahan,et al.  Hemophilia gene therapy: Update , 2002, Current opinion in hematology.

[24]  Kazunori Kataoka,et al.  PEGylated Nanoparticles for Biological and Pharmaceutical Applications , 2003 .

[25]  Dimitris Papamichail,et al.  Rational design of orthogonal libraries of protein coding genes. , 2013, ACS synthetic biology.

[26]  Özlem Türeci,et al.  mRNA-based therapeutics — developing a new class of drugs , 2014, Nature Reviews Drug Discovery.

[27]  H. Rammensee,et al.  Results of the First Phase I/II Clinical Vaccination Trial With Direct Injection of mRNA , 2008, Journal of immunotherapy.

[28]  Jesse K. Placone,et al.  Spontaneous membrane-translocating peptides by orthogonal high-throughput screening. , 2011, Journal of the American Chemical Society.

[29]  Fangxia Zhao,et al.  Orthogonal optimization design for preparation of Fe3O4 nanoparticles via chemical coprecipitation , 2013 .

[30]  N. Mabbott,et al.  Progress in Molecular Biology and Translational Science , 2017 .

[31]  M. Zoppè,et al.  A factor IX-deficient mouse model for hemophilia B gene therapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Mahlangu,et al.  Guidelines for the management of hemophilia , 2013, Haemophilia : the official journal of the World Federation of Hemophilia.

[33]  H. Rammensee,et al.  Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  S. D. De Smedt,et al.  mRNA as gene therapeutic: how to control protein expression. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[35]  Kyle E Broaders,et al.  Acid-degradable solid-walled microcapsules for pH-responsive burst-release drug delivery. , 2011, Chemical communications.

[36]  A. Coppola,et al.  Treatment of hemophilia: a review of current advances and ongoing issues , 2010, Journal of blood medicine.

[37]  Robert Langer,et al.  Degradable Lipid Nanoparticles with Predictable In Vivo siRNA Delivery Activity , 2014, Nature Communications.

[38]  H. Rammensee,et al.  Direct Injection of Protamine-protected mRNA: Results of a Phase 1/2 Vaccination Trial in Metastatic Melanoma Patients , 2009, Journal of immunotherapy.

[39]  S. Day,et al.  Murine thrombosis models , 2004, Thrombosis and Haemostasis.