Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges

RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical therapeutics requires the development of safe and effective delivery systems. Inspired by the immense progress with nanotechnology in drug delivery, efforts have been dedicated to the development of nanoparticle-based RNAi delivery systems. For example, a precisely engineered, multifunctional nanocarrier with combined passive and active targeting capabilities may address the delivery challenges for the widespread use of RNAi as a therapy. Therefore, in this review, we introduce the major hurdles in achieving efficient RNAi delivery and discuss the current advances in applying nanotechnology-based delivery systems to overcome the delivery hurdles of RNAi therapeutics. In particular, some representative examples of nanoparticle-based delivery formulations for targeted RNAi therapeutics are highlighted.

[1]  H. Gu,et al.  A mesoporous silica nanoparticle--PEI--fusogenic peptide system for siRNA delivery in cancer therapy. , 2013, Biomaterials.

[2]  V. Ceña,et al.  Dendrimers as vectors for genetic material delivery to the nervous system. , 2012, Current medicinal chemistry.

[3]  Peixuan Guo,et al.  Uniqueness, advantages, challenges, solutions, and perspectives in therapeutics applying RNA nanotechnology. , 2012, Nucleic acid therapeutics.

[4]  C. Alabi,et al.  Attacking the genome: emerging siRNA nanocarriers from concept to clinic. , 2012, Current opinion in pharmacology.

[5]  Juliane Nguyen,et al.  Nucleic acid delivery: the missing pieces of the puzzle? , 2012, Accounts of chemical research.

[6]  Huifang M. Zhang,et al.  Current advances in Phi29 pRNA biology and its application in drug delivery , 2012, Wiley interdisciplinary reviews. RNA.

[7]  B. Jessen,et al.  Retina expression and cross-species validation of gene silencing by PF-655, a small interfering RNA against RTP801 for the treatment of ocular disease. , 2012, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[8]  M Ferrari,et al.  Nanovector delivery of siRNA for cancer therapy , 2012, Cancer Gene Therapy.

[9]  S. Simões,et al.  Lipid-based nanoparticles for siRNA delivery in cancer therapy: paradigms and challenges. , 2012, Accounts of chemical research.

[10]  Jun Wang,et al.  Targeted Delivery of PLK1-siRNA by ScFv Suppresses Her2+ Breast Cancer Growth and Metastasis , 2012, Science Translational Medicine.

[11]  Paloma H. Giangrande,et al.  Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamers , 2012, Nucleic acids research.

[12]  T. Ohtsuki,et al.  Photoinduced RNA interference. , 2012, Accounts of chemical research.

[13]  J. Burnett,et al.  RNA-based therapeutics: current progress and future prospects. , 2012, Chemistry & biology.

[14]  K. Giese,et al.  Phase I clinical development of Atu027, a siRNA formulation targeting PKN3 in patients with advanced solid tumors. , 2012, International journal of clinical pharmacology and therapeutics.

[15]  D. Peer,et al.  Antibody-mediated delivery of siRNAs for anti-HIV therapy. , 2011, Methods in molecular biology.

[16]  Ling Peng,et al.  Systemic administration of combinatorial dsiRNAs via nanoparticles efficiently suppresses HIV-1 infection in humanized mice. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[17]  Xiaohu Gao,et al.  siRNA-aptamer chimeras on nanoparticles: preserving targeting functionality for effective gene silencing. , 2011, ACS nano.

[18]  X. Shuai,et al.  Hepatocyte-targeted psiRNA Delivery Mediated by Galactosylated Poly(Ethylene Glycol)-Graft-Polyethylenimine In Vitro , 2011, Journal of biomaterials applications.

[19]  Johannes Winkler.  Nanomedicines based on recombinant fusion proteins for targeting therapeutic siRNA oligonucleotides. , 2011, Therapeutic delivery.

[20]  S. Futaki,et al.  Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA. , 2011, Biomaterials.

[21]  R. Mahato,et al.  Extravasation of polymeric nanomedicines across tumor vasculature. , 2011, Advanced drug delivery reviews.

[22]  Won Jong Kim,et al.  Polymers in small-interfering RNA delivery. , 2011, Nucleic acid therapeutics.

[23]  Peixuan Guo,et al.  Thermodynamically Stable RNA three-way junctions as platform for constructing multi-functional nanoparticles for delivery of therapeutics , 2011, Nature Nanotechnology.

[24]  Afsaneh Lavasanifar,et al.  Traceable multifunctional micellar nanocarriers for cancer-targeted co-delivery of MDR-1 siRNA and doxorubicin. , 2011, ACS nano.

[25]  David D. Smith,et al.  Dual functional RNA nanoparticles containing phi29 motor pRNA and anti-gp120 aptamer for cell-type specific delivery and HIV-1 inhibition. , 2011, Methods.

[26]  Gert Storm,et al.  Endosomal escape pathways for delivery of biologicals. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[27]  Beverly L. Davidson,et al.  Current prospects for RNA interference-based therapies , 2011, Nature Reviews Genetics.

[28]  T. Park,et al.  Self-Assembled and Nanostructured siRNA Delivery Systems , 2011, Pharmaceutical Research.

[29]  Shuk-Mei Ho,et al.  Application of phi29 motor pRNA for targeted therapeutic delivery of siRNA silencing metallothionein-IIA and survivin in ovarian cancers. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[30]  N. Zhao,et al.  A nanocomplex that is both tumor cell-selective and cancer gene-specific for anaplastic large cell lymphoma , 2011, Journal of nanobiotechnology.

[31]  Peixuan Guo,et al.  Fabrication of stable and RNase-resistant RNA nanoparticles active in gearing the nanomotors for viral DNA packaging. , 2011, ACS nano.

[32]  Dai Fukumura,et al.  Multistage nanoparticle delivery system for deep penetration into tumor tissue , 2011, Proceedings of the National Academy of Sciences.

[33]  F. Lo‐Coco,et al.  Gemtuzumab ozogamicin for the treatment of acute promyelocytic leukemia: mechanisms of action and resistance, safety and efficacy , 2011, Expert opinion on biological therapy.

[34]  Daniel A. Balazs,et al.  Liposomes for Use in Gene Delivery , 2010, Journal of drug delivery.

[35]  S. Barik.  Intranasal Delivery of Antiviral siRNA , 2010, Methods in molecular biology.

[36]  M. Amarzguioui,et al.  A role for human Dicer in pre-RISC loading of siRNAs , 2010, Nucleic acids research.

[37]  A. Prochiantz,et al.  Penetratin story: an overview. , 2011, Methods in molecular biology.

[38]  Javier Guerra,et al.  Barriers to Non-Viral Vector-Mediated Gene Delivery in the Nervous System , 2011, Pharmaceutical Research.

[39]  Peixuan Guo.  The emerging field of RNA nanotechnology. , 2010, Nature nanotechnology.

[40]  John J Rossi,et al.  RNAi and small interfering RNAs in human disease therapeutic applications. , 2010, Trends in biotechnology.

[41]  Udo Bakowsky,et al.  Liposome-polyethylenimine complexes for enhanced DNA and siRNA delivery. , 2010, Biomaterials.

[42]  W. A. Yeudall,et al.  Dendrimer-triglycine-EGF nanoparticles for tumor imaging and targeted nucleic acid and drug delivery. , 2010, Oral oncology.

[43]  N. Svrzikapa,et al.  In vivo quantification of formulated and chemically modified small interfering RNA by heating-in-Triton quantitative reverse transcription polymerase chain reaction (HIT qRT-PCR) , 2010, Silence.

[44]  Joseph M. DeSimone,et al.  Strategies in the design of nanoparticles for therapeutic applications , 2010, Nature Reviews Drug Discovery.

[45]  J. Au,et al.  Delivery of siRNA Therapeutics: Barriers and Carriers , 2010, The AAPS Journal.

[46]  W. Chan,et al.  In vivo assembly of nanoparticle components to improve targeted cancer imaging , 2010, Proceedings of the National Academy of Sciences.

[47]  Zongxi Li,et al.  Mesoporous silica nanoparticles facilitate delivery of siRNA to shutdown signaling pathways in mammalian cells. , 2010, Small.

[48]  O. Feron,et al.  Tumor-Penetrating Peptides: A Shift from Magic Bullets to Magic Guns , 2010, Science Translational Medicine.

[49]  T. Yamaoka,et al.  Liver-targeted siRNA delivery by polyethylenimine (PEI)-pullulan carrier. , 2010, Bioorganic & medicinal chemistry.

[50]  Eunjung Kim,et al.  Prostate cancer cell death produced by the co-delivery of Bcl-xL shRNA and doxorubicin using an aptamer-conjugated polyplex. , 2010, Biomaterials.

[51]  Rob Lambkin-Williams,et al.  A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus , 2010, Proceedings of the National Academy of Sciences.

[52]  D. Dykxhoorn,et al.  Breaking down the barriers: siRNA delivery and endosome escape , 2010, Journal of Cell Science.

[53]  Mark E. Davis,et al.  Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles , 2010, Nature.

[54]  Matthias John,et al.  Polyethylenimine/small interfering RNA‐mediated knockdown of vascular endothelial growth factor in vivo exerts anti‐tumor effects synergistically with Bevacizumab , 2010, The journal of gene medicine.

[55]  Sudha Kumari,et al.  Endocytosis unplugged: multiple ways to enter the cell , 2010, Cell Research.

[56]  J. Rossi,et al.  Aptamer-targeted cell-specific RNA interference , 2010, Silence.

[57]  R. Langer,et al.  Lipid‐based nanotherapeutics for siRNA delivery , 2010, Journal of internal medicine.

[58]  Direct application of siRNA for in vivo pain research. , 2010, Methods in molecular biology.

[59]  R. Verma,et al.  Development of a targeted siRNA delivery system using FOL-PEG-PEI conjugate , 2010, Molecular Biology Reports.

[60]  Erkki Ruoslahti,et al.  Tissue-penetrating delivery of compounds and nanoparticles into tumors. , 2009, Cancer cell.

[61]  Mark E. Davis,et al.  Design and development of IT-101, a cyclodextrin-containing polymer conjugate of camptothecin. , 2009, Advanced drug delivery reviews.

[62]  Zheng-Rong Lu,et al.  Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier. , 2009, Biomaterials.

[63]  Anton P. McCaffrey,et al.  Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors , 2009, Nature Biotechnology.

[64]  Andrew Becker,et al.  Methotrexate delivery via folate targeted dendrimer-based nanotherapeutic platform. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[65]  O. Voinnet,et al.  Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity , 2009, Nature Cell Biology.

[66]  P. Sharp,et al.  Functional Delivery of siRNA in Mice Using Dendriworms , 2009, ACS nano.

[67]  T. Ohtsuki,et al.  Spatial regulation of specific gene expression through photoactivation of RNAi. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[68]  T. Ohtsuki,et al.  Cellular siRNA delivery using cell-penetrating peptides modified for endosomal escape. , 2009, Advanced drug delivery reviews.

[69]  Matthew Tirrell,et al.  Laser-Activated Gene Silencing via Gold Nanoshell-siRNA Conjugates. , 2009, ACS nano.

[70]  Yoon Yeo,et al.  Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. , 2009, Molecular pharmaceutics.

[71]  J. Ambati,et al.  Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth , 2009, Proceedings of the National Academy of Sciences.

[72]  Mark E. Davis.  The first targeted delivery of siRNA in humans via a self-assembling, cyclodextrin polymer-based nanoparticle: from concept to clinic. , 2009, Molecular pharmaceutics.

[73]  John J. Rossi,et al.  Selection, characterization and application of new RNA HIV gp 120 aptamers for facile delivery of Dicer substrate siRNAs into HIV infected cells , 2009, Nucleic acids research.

[74]  Ick Chan Kwon,et al.  Engineered polymers for advanced drug delivery. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[75]  Daniel G. Anderson,et al.  Knocking down barriers: advances in siRNA delivery , 2009, Nature Reviews Drug Discovery.

[76]  Kevin Kim,et al.  Silencing by small RNAs is linked to endosomal trafficking , 2009, Nature Cell Biology.

[77]  B. Wiedenmann,et al.  Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. , 2008, Cancer research.

[78]  T. Park,et al.  LHRH receptor-mediated delivery of siRNA using polyelectrolyte complex micelles self-assembled from siRNA-PEG-LHRH conjugate and PEI. , 2008, Bioconjugate chemistry.

[79]  S. Sieg,et al.  Faculty Opinions recommendation of T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. , 2008 .

[80]  Mark E. Davis,et al.  Nanoparticle therapeutics: an emerging treatment modality for cancer , 2008, Nature Reviews Drug Discovery.

[81]  Dale L. Greiner,et al.  T Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice , 2008, Cell.

[82]  Robert Langer,et al.  Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates , 2008, Proceedings of the National Academy of Sciences.

[83]  John J Rossi,et al.  Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[84]  Robert Langer,et al.  Nanotechnology and Aptamers: Applications in Drug Delivery , 2022 .

[85]  R. Juliano,et al.  Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides , 2008, Nucleic acids research.

[86]  C. Berry,et al.  Intracellular delivery of nanoparticles via the HIV-1 tat peptide. , 2008, Nanomedicine.

[87]  Ottrina S. Bond,et al.  Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes , 2008, Molecular vision.

[88]  L. Zhang,et al.  Nanoparticles in Medicine: Therapeutic Applications and Developments , 2008, Clinical pharmacology and therapeutics.

[89]  T. Ohtsuki,et al.  Cellular siRNA delivery mediated by a cell-permeant RNA-binding protein and photoinduced RNA interference. , 2008, Bioconjugate chemistry.

[90]  W. Monroe,et al.  Photoinduced RNA interference using DMNPE-caged 2'-deoxy-2'-fluoro substituted nucleic acids in vitro and in vivo. , 2008, Molecular bioSystems.

[91]  Justine R. Smith,et al.  Sequence- and target-independent angiogenesis suppression by siRNA via TLR3 , 2008, Nature.

[92]  J. Karp,et al.  Nanocarriers as an Emerging Platform for Cancer Therapy , 2022 .

[93]  T. Ohtsuki,et al.  Photo inducible RNA interference using cell permeable protein carrier. , 2007, Nucleic acids symposium series.

[94]  Cheng-Cai Zhang,et al.  Importance of size-to-charge ratio in construction of stable and uniform nanoscale RNA/dendrimer complexes. , 2007, Organic & biomolecular chemistry.

[95]  S. Dowdy,et al.  TAT transduction: the molecular mechanism and therapeutic prospects. , 2007, Trends in molecular medicine.

[96]  Ü. Langel,et al.  Delivery of short interfering RNA using endosomolytic cell‐penetrating peptides , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[97]  I. Zuhorn,et al.  Gene delivery by cationic lipids: in and out of an endosome. , 2007, Biochemical Society transactions.

[98]  Khaled Greish,et al.  Enhanced permeability and retention of macromolecular drugs in solid tumors: A royal gate for targeted anticancer nanomedicines , 2007, Journal of drug targeting.

[99]  O. Boerman,et al.  INTRAVENOUSLY ADMINISTERED SHORT INTERFERING RNA ACCUMULATES IN THE KIDNEY AND SELECTIVELY SUPPRESSES GENE FUNCTION IN RENAL PROXIMAL TUBULES , 2006, Drug Metabolism and Disposition.

[100]  Yong Wang,et al.  Cell type–specific delivery of siRNAs with aptamer-siRNA chimeras , 2006, Nature Biotechnology.

[101]  J. Rossi.  RNAi therapeutics: SNALPing siRNAs in vivo , 2006, Gene Therapy.

[102]  Alain Thierry,et al.  Endosome trapping limits the efficiency of splicing correction by PNA-oligolysine conjugates. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[103]  P. Nielsen,et al.  Photochemically enhanced cellular delivery of cell penetrating peptide‐PNA conjugates , 2006, FEBS letters.

[104]  B. Lebleu,et al.  Cell-penetrating peptide conjugates of peptide nucleic acids (PNA) as inhibitors of HIV-1 Tat-dependent trans-activation in cells , 2005, Nucleic acids research.

[105]  David P. Bartel,et al.  Passenger-Strand Cleavage Facilitates Assembly of siRNA into Ago2-Containing RNAi Enzyme Complexes , 2005, Cell.

[106]  P. Nielsen,et al.  Calcium ions effectively enhance the effect of antisense peptide nucleic acids conjugated to cationic tat and oligoarginine peptides. , 2005, Chemistry & biology.

[107]  A. J. Mixson,et al.  Highly branched HK peptides are effective carriers of siRNA , 2005, The journal of gene medicine.

[108]  J. Rossi.  RNAi and the P-body connection , 2005, Nature Cell Biology.

[109]  S Moein Moghimi,et al.  A two-stage poly(ethylenimine)-mediated cytotoxicity: implications for gene transfer/therapy. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[110]  Judy Lieberman,et al.  Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors , 2005, Nature Biotechnology.

[111]  H. Blau,et al.  Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies , 2005, Nature Cell Biology.

[112]  V. Torchilin.  Recent advances with liposomes as pharmaceutical carriers , 2005, Nature Reviews Drug Discovery.

[113]  P. Heegaard,et al.  Dendrimers in drug research. , 2004, Chemical Society reviews.

[114]  Mark E. Davis,et al.  Cyclodextrin-based pharmaceutics: past, present and future , 2004, Nature Reviews Drug Discovery.

[115]  J. M. Thomson,et al.  Argonaute2 Is the Catalytic Engine of Mammalian RNAi , 2004, Science.

[116]  T. Tuschl,et al.  Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. , 2004, Molecular cell.

[117]  Mark E. Davis,et al.  Cyclodextrin-modified polyethylenimine polymers for gene delivery. , 2004, Bioconjugate chemistry.

[118]  R. Schiffelers,et al.  Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. , 2004, Nucleic acids research.

[119]  Kinam Park,et al.  Polycation gene delivery systems: escape from endosomes to cytosol , 2003, The Journal of pharmacy and pharmacology.

[120]  H. Mizuguchi,et al.  Comparison of the efficiency and safety of non-viral vector-mediated gene transfer into a wide range of human cells. , 2002, Biological & pharmaceutical bulletin.

[121]  J. Adler-Moore,et al.  AmBisome: liposomal formulation, structure, mechanism of action and pre-clinical experience. , 2002, The Journal of antimicrobial chemotherapy.

[122]  A. Caudy,et al.  Argonaute2, a Link Between Genetic and Biochemical Analyses of RNAi , 2001, Science.

[123]  S M Moghimi,et al.  Long-circulating and target-specific nanoparticles: theory to practice. , 2001, Pharmacological reviews.

[124]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[125]  R. Jain,et al.  Role of extracellular matrix assembly in interstitial transport in solid tumors. , 2000, Cancer research.

[126]  P. Sharp,et al.  RNAi Double-Stranded RNA Directs the ATP-Dependent Cleavage of mRNA at 21 to 23 Nucleotide Intervals , 2000, Cell.

[127]  M. Famulok,et al.  Aptamers as tools in molecular biology and immunology. , 1999, Current topics in microbiology and immunology.

[128]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[129]  R K Jain,et al.  Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. , 1995, Cancer research.

[130]  D. Scherman,et al.  A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[131]  L. Gold,et al.  RNA pseudoknots that inhibit human immunodeficiency virus type 1 reverse transcriptase. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[132]  R K Jain,et al.  Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. , 1990, Cancer research.

[133]  R K Jain,et al.  Transport of molecules in the tumor interstitium: a review. , 1987, Cancer research.

[134]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.