Abstract
The recent progress in harnessing the efficient and precise method of DNA editing provided by CRISPR/Cas9 is one of the most promising major advances in the field of gene therapy. However, the development of safe and optimally efficient delivery systems for CRISPR/Cas9 elements capable of achieving specific targeting of gene therapy to the location of interest without off-target effects is a primary challenge for clinical therapeutics. Nanoparticles (NPs) provide a promising means to meet such challenges. In this review, we present the most recent advances in developing innovative NP-based delivery systems that efficiently deliver CRISPR/Cas9 constructs and maximize their effectiveness.
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Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product. J Bacteriol. 1987;169(12):5429–33.
Liu C, Zhang L, Liu H, Cheng K. Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications. J Control Release. 2017;266:17–26.
Jansen R, Embden JD, Gaastra W, Schouls LM. Identification of genes that are associated with DNA repeats in prokaryotes. Mol Microbiol. 2002;43(6):1565–75.
Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science. 2007;315(5819):1709–12.
Horvath P, Barrangou R. CRISPR/Cas, the immune system of bacteria and archaea. Science. 2010;327(5962):167–70.
Mojica FJ, Diez-Villasenor C, Garcia-Martinez J, Soria E. Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol. 2005;60(2):174–82.
Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.
Jinek M, East A, Cheng A, Lin S, Ma E, Doudna J. RNA-programmed genome editing in human cells. elife. 2013;2:e00471.
Stephens CJ, Kashentseva E, Everett W, Kaliberova L, Curiel DT. Targeted in vivo knock-in of human alpha-1-antitrypsin cDNA using adenoviral delivery of CRISPR/Cas9. Gene Ther. 2018.
Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 2014;346(6213):1258096.
Deltcheva E, Chylinski K, Sharma CM, Gonzales K, Chao Y, Pirzada ZA, et al. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature. 2011;471(7340):602–7.
Wang H, La Russa M, Qi LS. CRISPR/Cas9 in genome editing and beyond. Annu Rev Biochem. 2016;85:227–64.
Li L, Hu S, Chen X. Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities. Biomaterials. 2018;171:207–18.
Yin H, Kauffman KJ, Anderson DG. Delivery technologies for genome editing. Nat Rev Drug Discov. 2017;16(6):387–99.
Makarova KS, Haft DH, Barrangou R, Brouns SJ, Charpentier E, Horvath P, et al. Evolution and classification of the CRISPR-Cas systems. Nat Rev Microbiol. 2011;9(6):467–77.
Cyranoski D. First trial of CRISPR in people. Nature. 2016;535(7613):476–7.
Xu Z, Chen L, Gu W, Gao Y, Lin L, Zhang Z, et al. The performance of docetaxel-loaded solid lipid nanoparticles targeted to hepatocellular carcinoma. Biomaterials. 2009;30(2):226–32.
Aldayel AM, Naguib YW, O'Mary HL, Li X, Niu M, Ruwona TB, et al. Acid-sensitive sheddable PEGylated PLGA nanoparticles increase the delivery of TNF-alpha siRNA in chronic inflammation sites. Mol Ther Nucleic Acids. 2016;5(7):e340.
Naguib YW, Cui Z. Nanomedicine: the promise and challenges in cancer chemotherapy. Adv Exp Med Biol. 2014;811:207–33.
Rajasekaran D, Srivastava J, Ebeid K, Gredler R, Akiel M, Jariwala N, et al. Combination of nanoparticle-delivered siRNA for astrocyte elevated gene-1 (AEG-1) and all-trans retinoic acid (ATRA): an effective therapeutic strategy for hepatocellular carcinoma (HCC). Bioconjug Chem. 2015;26(8):1651–61.
Givens BE, Geary SM, Salem AK. Nanoparticle-based CpG-oligonucleotide therapy for treating allergic asthma. Immunotherapy. 2018.
Ebeid K, Meng X, Thiel KW, Do AV, Geary SM, Morris AS, et al. Synthetically lethal nanoparticles for treatment of endometrial cancer. Nat Nanotechnol. 2018;13(1):72–81.
Wongrakpanich A, Morris AS, Geary SM, Joiner MA, Salem AK. Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury. Int J Pharm. 2017;520(1–2):275–83.
Morris AS, Sebag SC, Paschke JD, Wongrakpanich A, Ebeid K, Anderson ME, et al. Cationic CaMKII inhibiting nanoparticles prevent allergic asthma. Mol Pharm. 2017;14(6):2166–75.
Joshi VB, Adamcakova-Dodd A, Jing X, Wongrakpanich A, Gibson-Corley KN, Thorne PS, et al. Development of a poly (lactic-co-glycolic acid) particle vaccine to protect against house dust mite induced allergy. AAPS J. 2014;16(5):975–85.
Joshi VB, Geary SM, Salem AK. Biodegradable particles as vaccine delivery systems: size matters. AAPS J. 2013;15(1):85–94.
Salem AK, Searson PC, Leong KW. Multifunctional nanorods for gene delivery. Nat Mater. 2003;2(10):668–71.
Wang HX, Li M, Lee CM, Chakraborty S, Kim HW, Bao G, et al. CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery. Chem Rev. 2017;117(15):9874–906.
Wang HX, Song Z, Lao YH, Xu X, Gong J, Cheng D, et al. Nonviral gene editing via CRISPR/Cas9 delivery by membrane-disruptive and endosomolytic helical polypeptide. Proc Natl Acad Sci U S A. 2018.
Paliwal R, Babu RJ, Palakurthi S. Nanomedicine scale-up technologies: feasibilities and challenges. AAPS PharmSciTech. 2014;15(6):1527–34.
Glass Z, Lee M, Li Y, Xu Q. Engineering the delivery system for CRISPR-based genome editing. Trends Biotechnol. 2018;36(2):173–85.
Lostale-Seijo I, Louzao I, Juanes M, Montenegro J. Peptide/Cas9 nanostructures for ribonucleoprotein cell membrane transport and gene edition. Chem Sci. 2017;8(12):7923–31.
Mekler V, Minakhin L, Semenova E, Kuznedelov K, Severinov K. Kinetics of the CRISPR-Cas9 effector complex assembly and the role of 3′-terminal segment of guide RNA. Nucleic Acids Res. 2016;44(6):2837–45.
DiCarlo JE, Deeconda A, Tsang SH. Viral vectors, engineered cells and the CRISPR revolution. Adv Exp Med Biol. 2017;1016:3–27.
Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121):823–6.
Hess GT, Tycko J, Yao D, Bassik MC. Methods and applications of CRISPR-mediated base editing in eukaryotic genomes. Mol Cell. 2017;68(1):26–43.
Wang M, Glass ZA, Xu Q. Non-viral delivery of genome-editing nucleases for gene therapy. Gene Ther. 2017;24(3):144–50.
Ha JS, Lee JS, Jeong J, Kim H, Byun J, Kim SA, et al. Poly-sgRNA/siRNA ribonucleoprotein nanoparticles for targeted gene disruption. J Control Release. 2017;250:27–35.
Mout R, Ray M, Lee YW, Scaletti F, Rotello VM. In vivo delivery of CRISPR/Cas9 for therapeutic gene editing: progress and challenges. Bioconjug Chem. 2017;28(4):880–4.
Khalil IA, Kogure K, Futaki S, Hama S, Akita H, Ueno M, et al. Octaarginine-modified multifunctional envelope-type nanoparticles for gene delivery. Gene Ther. 2007;14(8):682–9.
Xu S, Olenyuk BZ, Okamoto CT, Hamm-Alvarez SF. Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv Drug Deliv Rev. 2013;65(1):121–38.
Akinc A, Thomas M, Klibanov AM, Langer R. Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J Gene Med. 2005;7(5):657–63.
Vercauteren D, Rejman J, Martens TF, Demeester J, De Smedt SC, Braeckmans K. On the cellular processing of non-viral nanomedicines for nucleic acid delivery: mechanisms and methods. J Control Release. 2012;161(2):566–81.
Sonawane ND, Szoka FC, Jr., Verkman AS. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem 2003;278(45):44826–44831.
Richard I, Thibault M, De Crescenzo G, Buschmann MD, Lavertu M. Ionization behavior of chitosan and chitosan-DNA polyplexes indicate that chitosan has a similar capability to induce a proton-sponge effect as PEI. Biomacromolecules. 2013;14(6):1732–40.
Cardarelli F, Pozzi D, Bifone A, Marchini C, Caracciolo G. Cholesterol-dependent macropinocytosis and endosomal escape control the transfection efficiency of lipoplexes in CHO living cells. Mol Pharm. 2012;9(2):334–40.
Kalderon D, Roberts BL, Richardson WD, Smith AE. A short amino acid sequence able to specify nuclear location. Cell. 1984;39(3 Pt 2):499–509.
Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH. Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem. 2007;282(8):5101–5.
Sun Y, Xian L, Xing H, Yu J, Yang Z, Yang T, et al. Factors influencing the nuclear targeting ability of nuclear localization signals. J Drug Target. 2016;24(10):927–33.
Hu Q, Wang J, Shen J, Liu M, Jin X, Tang G, et al. Intracellular pathways and nuclear localization signal peptide-mediated gene transfection by cationic polymeric nanovectors. Biomaterials. 2012;33(4):1135–45.
Lee J, Jung J, Kim YJ, Lee E, Choi JS. Gene delivery of PAMAM dendrimer conjugated with the nuclear localization signal peptide originated from fibroblast growth factor 3. Int J Pharm. 2014;459(1–2):10–8.
Park E, Cho HB, Takimoto K. Effective gene delivery into adipose-derived stem cells: transfection of cells in suspension with the use of a nuclear localization signal peptide-conjugated polyethylenimine. Cytotherapy. 2015;17(5):536–42.
Pan L, He Q, Liu J, Chen Y, Ma M, Zhang L, et al. Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nanoparticles. J Am Chem Soc. 2012;134(13):5722–5.
Malhotra M, Tomaro-Duchesneau C, Prakash S. Synthesis of TAT peptide-tagged PEGylated chitosan nanoparticles for siRNA delivery targeting neurodegenerative diseases. Biomaterials. 2013;34(4):1270–80.
Nitin N, LaConte L, Rhee WJ, Bao G. Tat peptide is capable of importing large nanoparticles across nuclear membrane in digitonin permeabilized cells. Ann Biomed Eng. 2009;37(10):2018–27.
Ammosova T, Jerebtsova M, Beullens M, Lesage B, Jackson A, Kashanchi F, et al. Nuclear targeting of protein phosphatase-1 by HIV-1 Tat protein. J Biol Chem. 2005;280(43):36364–71.
Sandgren S, Cheng F, Belting M. Nuclear targeting of macromolecular polyanions by an HIV-Tat derived peptide. Role for cell-surface proteoglycans. J Biol Chem. 2002;277(41):38877–83.
Liu BY, He XY, Xu C, Xu L, Ai SL, Cheng SX, et al. A dual-targeting delivery system for effective genome editing and in situ detecting related protein expression in edited cells. Biomacromolecules. 2018.
Asai T, Tsuzuku T, Takahashi S, Okamoto A, Dewa T, Nango M, et al. Cell-penetrating peptide-conjugated lipid nanoparticles for siRNA delivery. Biochem Biophys Res Commun 2014;444(4):599–604.
Nelson CE, Gersbach CA. Engineering delivery vehicles for genome editing. Annu Rev Chem Biomol Eng. 2016;7:637–62.
Cardarelli F, Digiacomo L, Marchini C, Amici A, Salomone F, Fiume G, et al. The intracellular trafficking mechanism of Lipofectamine-based transfection reagents and its implication for gene delivery. Sci Rep. 2016;6:25879.
Yu X, Liang X, Xie H, Kumar S, Ravinder N, Potter J, et al. Improved delivery of Cas9 protein/gRNA complexes using lipofectamine CRISPRMAX. Biotechnol Lett. 2016;38(6):919–29.
Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–23.
Ebina H, Misawa N, Kanemura Y, Koyanagi Y. Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. Sci Rep. 2013;3:2510.
Liang X, Potter J, Kumar S, Zou Y, Quintanilla R, Sridharan M, et al. Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection. J Biotechnol. 2015;208:44–53.
Daubendiek SL, Kool ET. Generation of catalytic RNAs by rolling transcription of synthetic DNA nanocircles. Nat Biotechnol. 1997;15(3):273–7.
Daubendiek SL, Ryan K, Kool ET. Rolling-circle RNA synthesis: circular oligonucleotides as efficient substrates for T7 RNA polymerase. J Am Chem Soc. 1995;117(29):7818–9.
Kim H, Park Y, Lee JB. Self-assembled messenger RNA nanoparticles (mRNA-NPs) for efficient gene expression. Sci Rep. 2015;5:12737.
Lee JB, Hong J, Bonner DK, Poon Z, Hammond PT. Self-assembled RNA interference microsponges for efficient siRNA delivery. Nat Mater. 2012;11(4):316–22.
Sharma B, Crist RM, Adiseshaiah PP. Nanotechnology as a delivery tool for precision cancer therapies. AAPS J. 2017.
del Pozo-Rodriguez A, Delgado D, Solinis MA, Pedraz JL, Echevarria E, Rodriguez JM, et al. Solid lipid nanoparticles as potential tools for gene therapy: in vivo protein expression after intravenous administration. Int J Pharm. 2010;385(1–2):157–62.
Radaic A, de Paula E, de Jesus MB. Factorial design and development of solid lipid nanoparticles (SLN) for gene delivery. J Nanosci Nanotechnol. 2015;15(2):1793–800.
Sune-Pou M, Prieto-Sanchez S, El Yousfi Y, Boyero-Corral S, Nardi-Ricart A, Nofrerias-Roig I, et al. Cholesteryl oleate-loaded cationic solid lipid nanoparticles as carriers for efficient gene-silencing therapy. Int J Nanomedicine. 2018;13:3223–33.
Akinc A, Querbes W, De S, Qin J, Frank-Kamenetsky M, Jayaprakash KN, et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 2010;18(7):1357–64.
Wang P, Zhang L, Xie Y, Wang N, Tang R, Zheng W, et al. Genome editing for cancer therapy: delivery of Cas9 protein/sgRNA plasmid via a gold nanocluster/lipid core-shell nanocarrier. Advanced Science 2017.
Zheng T, Bott S, Huo Q. Techniques for accurate sizing of gold nanoparticles using dynamic light scattering with particular application to chemical and biological sensing based on aggregate formation. ACS Appl Mater Interfaces. 2016;8(33):21585–94.
Yin H, Song CQ, Suresh S, Wu Q, Walsh S, Rhym LH, et al. Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing. Nat Biotechnol. 2017.
Dong Y, Love KT, Dorkin JR, Sirirungruang S, Zhang Y, Chen D, et al. Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates. Proc Natl Acad Sci U S A. 2014;111(11):3955–60.
Wang M, Zuris JA, Meng F, Rees H, Sun S, Deng P, et al. Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles. Proc Natl Acad Sci U S A. 2016;113(11):2868–73.
Li Y, Yang T, Yu Y, Shi N, Yang L, Glass Z, et al. Combinatorial library of chalcogen-containing lipidoids for intracellular delivery of genome-editing proteins. Biomaterials 2018.
Zhen S, Takahashi Y, Narita S, Yang YC, Li X. Targeted delivery of CRISPR/Cas9 to prostate cancer by modified gRNA using a flexible aptamer-cationic liposome. Oncotarget. 2017;8(6):9375–87.
Finn JD, Smith AR, Patel MC, Shaw L, Youniss MR, van Heteren J, et al. A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing. Cell Rep. 2018;22(9):2227–35.
Miller JB, Zhang S, Kos P, Xiong H, Zhou K, Perelman SS, et al. Non-viral CRISPR/Cas gene editing in vitro and in vivo enabled by synthetic nanoparticle co-delivery of Cas9 mRNA and sgRNA. Angew Chem Int Ed Engl. 2017;56(4):1059–63.
Mout R, Ray M, Yesilbag Tonga G, Lee YW, Tay T, Sasaki K, et al. Direct cytosolic delivery of CRISPR/Cas9-ribonucleoprotein for efficient gene editing. ACS Nano. 2017;11(3):2452–8.
Alsaiari SK, Patil S, Alyami M, Alamoudi KO, Aleisa FA, Merzaban JS, et al. Endosomal escape and delivery of CRISPR/Cas9 genome editing machinery enabled by nanoscale zeolitic imidazolate framework. J Am Chem Soc. 2018;140(1):143–6.
Yue H, Zhou X, Cheng M, Xing D. Graphene oxide-mediated Cas9/sgRNA delivery for efficient genome editing. Nanoscale. 2018;10(3):1063–71.
Sun W, Ji W, Hall JM, Hu Q, Wang C, Beisel CL, et al. Self-assembled DNA nanoclews for the efficient delivery of CRISPR-Cas9 for genome editing. Angew Chem Int Ed Engl. 2015;54(41):12029–33.
Kretzmann JA, Ho D, Evans CW, Plani-Lam JHC, Garcia-Bloj B, Mohamed AE, et al. Synthetically controlling dendrimer flexibility improves delivery of large plasmid DNA. Chem Sci. 2017;8(4):2923–30.
Akinc A, Zumbuehl A, Goldberg M, Leshchiner ES, Busini V, Hossain N, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol. 2008;26(5):561–9.
Wang M, Alberti K, Sun S, Arellano CL, Xu Q. Combinatorially designed lipid-like nanoparticles for intracellular delivery of cytotoxic protein for cancer therapy. Angew Chem Int Ed Engl. 2014;53(11):2893–8.
Li B, Dong Y. Preparation and optimization of lipid-like nanoparticles for mRNA delivery. Methods Mol Biol. 1632;2017:207–17.
Li B, Luo X, Deng B, Giancola JB, McComb DW, Schmittgen TD, et al. Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Sci Rep 2016;6:22137.
Love KT, Mahon KP, Levins CG, Whitehead KA, Querbes W, Dorkin JR, et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc Natl Acad Sci U S A. 2010;107(5):1864–9.
Whitehead KA, Dorkin JR, Vegas AJ, Chang PH, Veiseh O, Matthews J, et al. Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity. Nat Commun. 2014;5:4277.
Pombo Garcia K, Zarschler K, Barbaro L, Barreto JA, O'Malley W, Spiccia L, et al. Zwitterionic-coated “stealth” nanoparticles for biomedical applications: recent advances in countering biomolecular corona formation and uptake by the mononuclear phagocyte system. Small. 2014;10(13):2516–29.
Panayiotou E, Papacharalambous R, Antoniou A, Christophides G, Papageorgiou L, Fella E, et al. Genetic background modifies amyloidosis in a mouse model of ATTR neuropathy. Biochem Biophys Rep. 2016;8:48–54.
Langer R, Folkman J. Polymers for the sustained release of proteins and other macromolecules. Nature. 1976;263(5580):797–800.
Leelakanok N, Geary SM, Salem AK. Antitumor efficacy and toxicity of 5-fluorouracil-loaded poly(lactide co-glycolide) pellets. J Pharm Sci. 2018;107(2):690–7.
Coleman MC, Goetz JE, Brouillette MJ, Seol D, Willey MC, Petersen EB, et al. Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis. Sci Transl Med. 2018;10(427).
Wafa EI, Geary SM, Goodman JT, Narasimhan B, Salem AK. The effect of polyanhydride chemistry in particle-based cancer vaccines on the magnitude of the anti-tumor immune response. Acta Biomater. 2017;50:417–27.
Khorsand B, Elangovan S, Hong L, Dewerth A, Kormann MS, Salem AK. A comparative study of the bone regenerative effect of chemically modified RNA encoding BMP-2 or BMP-9. AAPS J. 2017;19(2):438–46.
Salem AK. Nanoparticles in vaccine delivery. AAPS J. 2015;17(2):289–91.
Makkouk A, Joshi VB, Wongrakpanich A, Lemke CD, Gross BP, Salem AK, et al. Biodegradable microparticles loaded with doxorubicin and CpG ODN for in situ immunization against cancer. AAPS J. 2015;17(1):184–93.
Geary SM, Hu Q, Joshi VB, Bowden NB, Salem AK. Diaminosulfide based polymer microparticles as cancer vaccine delivery systems. J Control Release. 2015;220(Pt B):682–90.
Wongrakpanich A, Adamcakova-Dodd A, Xie W, Joshi VB, Mapuskar KA, Geary SM, et al. The absence of CpG in plasmid DNA-chitosan polyplexes enhances transfection efficiencies and reduces inflammatory responses in murine lungs. Mol Pharm. 2014;11(3):1022–31.
Gross BP, Wongrakpanich A, Francis MB, Salem AK, Norian LA. A therapeutic microparticle-based tumor lysate vaccine reduces spontaneous metastases in murine breast cancer. AAPS J. 2014;16(6):1194–203.
Joshi VB, Geary SM, Carrillo-Conde BR, Narasimhan B, Salem AK. Characterizing the antitumor response in mice treated with antigen-loaded polyanhydride microparticles. Acta Biomater. 2013;9(3):5583–9.
Hong L, Wei N, Joshi V, Yu Y, Kim N, Krishnamachari Y, et al. Effects of glucocorticoid receptor small interfering RNA delivered using poly lactic-co-glycolic acid microparticles on proliferation and differentiation capabilities of human mesenchymal stromal cells. Tissue Eng Part A. 2012;18(7–8):775–84.
Krishnamachari Y, Geary SM, Lemke CD, Salem AK. Nanoparticle delivery systems in cancer vaccines. Pharm Res. 2011;28(2):215–36.
Intra J, Salem AK. Rational design, fabrication, characterization and in vitro testing of biodegradable microparticles that generate targeted and sustained transgene expression in HepG2 liver cells. J Drug Target. 2011;19(6):393–408.
Intra J, Salem AK. Fabrication, characterization and in vitro evaluation of poly(D,L-lactide-co-glycolide) microparticles loaded with polyamidoamine-plasmid DNA dendriplexes for applications in nonviral gene delivery. J Pharm Sci. 2010;99(1):368–84.
Zhang XQ, Intra J, Salem AK. Comparative study of poly (lactic-co-glycolic acid)-poly ethyleneimine-plasmid DNA microparticles prepared using double emulsion methods. J Microencapsul. 2008;25(1):1–12.
Abbas AO, Donovan MD, Salem AK. Formulating poly(lactide-co-glycolide) particles for plasmid DNA delivery. J Pharm Sci. 2008;97(7):2448–61.
Intra J, Salem AK. Characterization of the transgene expression generated by branched and linear polyethylenimine-plasmid DNA nanoparticles in vitro and after intraperitoneal injection in vivo. J Control Release. 2008;130(2):129–38.
Zhang XQ, Intra J, Salem AK. Conjugation of polyamidoamine dendrimers on biodegradable microparticles for nonviral gene delivery. Bioconjug Chem. 2007;18(6):2068–76.
Behzadi S, Serpooshan V, Tao W, Hamaly MA, Alkawareek MY, Dreaden EC, et al. Cellular uptake of nanoparticles: journey inside the cell. Chem Soc Rev. 2017;46(14):4218–44.
Wongrakpanich A, Wu M, Salem AK. Correlating intracellular nonviral polyplex localization with transfection efficiency using high-content screening. Biotechnol Prog. 2015;31(6):1685–92.
Atluri K, Seabold D, Hong L, Elangovan S, Salem AK. Nanoplex-mediated codelivery of fibroblast growth factor and bone morphogenetic protein genes promotes osteogenesis in human adipocyte-derived mesenchymal stem cells. Mol Pharm. 2015;12(8):3032–42.
Ganas C, Weiss A, Nazarenus M, Rosler S, Kissel T, Rivera Gil P, et al. Biodegradable capsules as non-viral vectors for in vitro delivery of PEI/siRNA polyplexes for efficient gene silencing. J Control Release. 2014;196:132–8.
Li L, He ZY, Wei XW, Gao GP, Wei YQ. Challenges in CRISPR/CAS9 delivery: potential roles of nonviral vectors. Hum Gene Ther. 2015;26(7):452–62.
Francis SM, Taylor CA, Tang T, Liu Z, Zheng Q, Dondero R, et al. SNS01-T modulation of eIF5A inhibits B-cell cancer progression and synergizes with bortezomib and lenalidomide. Mol Ther. 2014;22(9):1643–52.
Suenaga T, Kohyama M, Hirayasu K, Arase H. Engineering large viral DNA genomes using the CRISPR-Cas9 system. Microbiol Immunol. 2014;58(9):513–22.
Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15(8):541–55.
Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005;4(7):581–93.
Campeau P, Chapdelaine P, Seigneurin-Venin S, Massie B, Tremblay JP. Transfection of large plasmids in primary human myoblasts. Gene Ther. 2001;8(18):1387–94.
Wang M, Liu H, Li L, Cheng Y. A fluorinated dendrimer achieves excellent gene transfection efficacy at extremely low nitrogen to phosphorus ratios. Nat Commun. 2014;5:3053.
Beerli RR, Segal DJ, Dreier B, Barbas CF 3rd. Toward controlling gene expression at will: specific regulation of the erbB-2/HER-2 promoter by using polydactyl zinc finger proteins constructed from modular building blocks. Proc Natl Acad Sci U S A. 1998;95(25):14628–33.
Worthington KS, Green BJ, Rethwisch M, Wiley LA, Tucker BA, Guymon CA, et al. Neuronal differentiation of induced pluripotent stem cells on surfactant templated chitosan hydrogels. Biomacromolecules. 2016;17(5):1684–95.
Mahiny AJ, Dewerth A, Mays LE, Alkhaled M, Mothes B, Malaeksefat E, et al. In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency. Nat Biotechnol. 2015;33(6):584–6.
Wilder MA. Surfactant protein B deficiency in infants with respiratory failure. J Perinat Neonat Nurs. 2004;18(1):61–7.
Liu Y, Wang T, He F, Liu Q, Zhang D, Xiang S, et al. An efficient calcium phosphate nanoparticle-based nonviral vector for gene delivery. Int J Nanomedicine. 2011;6:721–7.
Ge X, Zhang Q, Cai Y, Duan S, Chen S, Lv N, et al. PEG-PCL-DEX polymersome-protamine vector as an efficient gene delivery system via PEG-guided self-assembly. Nanomedicine (Lond). 2014;9(8):1193–207.
Puras G, Martinez-Navarrete G, Mashal M, Zarate J, Agirre M, Ojeda E, et al. Protamine/DNA/Niosome ternary nonviral vectors for gene delivery to the retina: the role of protamine. Mol Pharm. 2015;12(10):3658–71.
Yang W, Cheng Y, Xu T, Wang X, Wen LP. Targeting cancer cells with biotin-dendrimer conjugates. Eur J Med Chem. 2009;44(2):862–8.
Vineberg JG, Zuniga ES, Kamath A, Chen YJ, Seitz JD, Ojima I. Design, synthesis, and biological evaluations of tumor-targeting dual-warhead conjugates for a taxoid-camptothecin combination chemotherapy. J Med Chem. 2014;57(13):5777–91.
Koutsioumpa M, Papadimitriou E. Cell surface nucleolin as a target for anti-cancer therapies. Recent Pat Anticancer Drug Discov. 2014;9(2):137–52.
Sinclair JF, O'Brien AD. Cell surface-localized nucleolin is a eukaryotic receptor for the adhesin intimin-gamma of enterohemorrhagic Escherichia coli O157:H7. J Biol Chem. 2002;277(4):2876–85.
Zhou Y, Han C, Li D, Yu Z, Li F, Li F, et al. Cyclin-dependent kinase 11(p110) (CDK11(p110)) is crucial for human breast cancer cell proliferation and growth. Sci Rep. 2015;5:10433.
Liu X, Gao Y, Shen J, Yang W, Choy E, Mankin H, et al. Cyclin-dependent kinase 11 (CDK11) is required for ovarian cancer cell growth in vitro and in vivo, and its inhibition causes apoptosis and sensitizes cells to paclitaxel. Mol Cancer Ther. 2016;15(7):1691–701.
Feng Y, Sassi S, Shen JK, Yang X, Gao Y, Osaka E, et al. Targeting CDK11 in osteosarcoma cells using the CRISPR-Cas9 system. J Orthop Res. 2015;33(2):199–207.
Hoyer J, Neundorf I. Peptide vectors for the nonviral delivery of nucleic acids. Acc Chem Res. 2012;45(7):1048–56.
Guo Z, Peng H, Kang J, Sun D. Cell-penetrating peptides: possible transduction mechanisms and therapeutic applications. Biomed Rep. 2016;4(5):528–34.
Radis-Baptista G, Campelo IS, Morlighem JRL, Melo LM, Freitas VJF. Cell-penetrating peptides (CPPs): from delivery of nucleic acids and antigens to transduction of engineered nucleases for application in transgenesis. J Biotechnol. 2017;252:15–26.
Li H, Tsui TY, Ma W. Intracellular delivery of molecular cargo using cell-penetrating peptides and the combination strategies. Int J Mol Sci. 2015;16(8):19518–36.
Ramakrishna S, Kwaku Dad AB, Beloor J, Gopalappa R, Lee SK, Kim H. Gene disruption by cell-penetrating peptide-mediated delivery of Cas9 protein and guide RNA. Genome Res. 2014;24(6):1020–7.
Yamashita H, Kato T, Oba M, Misawa T, Hattori T, Ohoka N, et al. Development of a cell-penetrating peptide that exhibits responsive changes in its secondary structure in the cellular environment. Sci Rep. 2016;6:33003.
Jeong EJ, Choi M, Lee J, Rhim T, Lee KY. The spacer arm length in cell-penetrating peptides influences chitosan/siRNA nanoparticle delivery for pulmonary inflammation treatment. Nanoscale. 2015;7(47):20095–104.
Chaterji S, Ahn EH, Kim DH. CRISPR genome engineering for human pluripotent stem cell research. Theranostics. 2017;7(18):4445–69.
Gabrielson NP, Lu H, Yin L, Li D, Wang F, Cheng J. Reactive and bioactive cationic alpha-helical polypeptide template for nonviral gene delivery. Angew Chem Int Ed Engl. 2012;51(5):1143–7.
He H, Zheng N, Song Z, Kim KH, Yao C, Zhang R, et al. Suppression of hepatic inflammation via systemic siRNA delivery by membrane-disruptive and endosomolytic helical polypeptide hybrid nanoparticles. ACS Nano. 2016;10(2):1859–70.
Lu H, Wang J, Bai Y, Lang JW, Liu S, Lin Y, et al. Ionic polypeptides with unusual helical stability. Nat Commun. 2011;2:206.
Zheng N, Song Z, Yang J, Liu Y, Li F, Cheng J, et al. Manipulating the membrane penetration mechanism of helical polypeptides via aromatic modification for efficient gene delivery. Acta Biomater. 2017;58:146–57.
Vert M, Doi Y, Hellwich KH, Hess M, Hodge P, Kubisa P, et al. Terminology for biorelated polymers and applications (IUPAC recommendations 2012). Pure Appl Chem. 2012;84(2):377–408.
Yang J, Bahreman A, Daudey G, Bussmann J, Olsthoorn RC, Kros A. Drug delivery via cell membrane fusion using lipopeptide modified liposomes. ACS Cent Sci. 2016;2(9):621–30.
Lee K, Conboy M, Park HM, Jiang F, Kim HJ, Dewitt MA, et al. Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair. Nat Biomed Eng. 2017;1:889–901.
Lu C, Stewart DJ, Lee JJ, Ji L, Ramesh R, Jayachandran G, et al. Phase I clinical trial of systemically administered TUSC2(FUS1)-nanoparticles mediating functional gene transfer in humans. PLoS One. 2012;7(4):e34833.
Phase I Study of IV DOTAP: cholesterol-Fus1 in non-small-cell lung cancer [Available from: https://ClinicalTrials.gov/show/NCT00059605.
Study of PNT2258 for Treatment of Relapsed or Refractory Non-Hodgkin's Lymphoma [Available from: https://ClinicalTrials.gov/show/NCT01733238.
A Study of PNT2258 in Patients With Advanced Solid Tumors [Available from: https://ClinicalTrials.gov/show/NCT01191775.
Harb WA, Lakhani N, Logsdon A, Steigelman M, Smith-Green H, Gaylor S, et al. The BCL2 targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 is active in patients with relapsed or refractory non-Hodgkin’s lymphoma. Blood. 2014;124(21):1716.
Tolcher AW, Rodrigueza WV, Rasco DW, Patnaik A, Papadopoulos KP, Amaya A, et al. A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014;73(2):363–71.
Safety and Tolerability Study of SNS01-T in Relapsed or Refractory B Cell Malignancies (Multiple Myeloma, B Cell Lymphoma, or Plasma Cell Leukemia (PCL) [Available from: https://ClinicalTrials.gov/show/NCT01435720.
Siegel DS, McDonald A, Novitzky N, Bensinger W, Craig M, van Rhee F, et al. Mature results of a phase 1-2 open-label, dose-escalation study of intravenous SNS01-T in patients (pts) with relapsed or refractory B-cell malignancies. Blood. 2014;124(21):4464.
Pilot Study of BC-819/PEI and BCG in Patients With Superficial Transitional Cell Bladder Carcinoma [Available from: https://ClinicalTrials.gov/show/NCT01878188.
Phase 1/2a Study of DTA-H19 in Advanced Stage Ovarian Cancer [Available from: https://ClinicalTrials.gov/show/NCT00826150.
Lavie O, Edelman D, Levy T, Fishman A, Hubert A, Segev Y, et al. A phase 1/2a, dose-escalation, safety, pharmacokinetic, and preliminary efficacy study of intraperitoneal administration of BC-819 (H19-DTA) in subjects with recurrent ovarian/peritoneal cancer. Arch Gynecol Obstet. 2017;295(3):751–61.
Sidi AA, Ohana P, Benjamin S, Shalev M, Ransom JH, Lamm D, et al. Phase I/II marker lesion study of intravesical BC-819 DNA plasmid in H19 over expressing superficial bladder cancer refractory to bacillus Calmette-Guerin. J Urol. 2008;180(6):2379–83.
Study With Atu027 in Patients With Advanced Solid Cancer [Available from: https://ClinicalTrials.gov/show/NCT00938574.
Atu027 Plus Gemcitabine in Advanced or Metastatic Pancreatic Cancer (Atu027-I-02) [Available from: https://ClinicalTrials.gov/show/NCT01808638.
Aleku M, Schulz P, Keil O, Santel A, Schaeper U, Dieckhoff B, et al. Atu027, a liposomal small interfering RNA formulation targeting protein kinase N3, inhibits cancer progression. Cancer Res. 2008;68(23):9788–98.
Schultheis B, Strumberg D, Kuhlmann J, Wolf M, Link K, Seufferlein T, et al. A phase Ib/IIa study of combination therapy with gemcitabine and Atu027 in patients with locally advanced or metastatic pancreatic adenocarcinoma. J Clin Oncol. 2016;34(4_suppl):385.
Schultheis B, Strumberg D, Santel A, Vank C, Gebhardt F, Keil O, et al. First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors. J Clin Oncol. 2014;32(36):4141–8.
Silence T. Pancreatic cancer study Atu027-I-02 Interim analysis 2015 [Available from: https://www.silence-therapeutics.com/media/1263/atu027-phase-2a-pancreatic-cancer-interim-analysis.pdf.
Phase I, Multicenter, dose escalation study of DCR-MYC in patients with solid tumors, multiple myeloma, or lymphoma [Available from: https://ClinicalTrials.gov/show/NCT02110563.
Tolcher AW, Papadopoulos KP, Patnaik A, Rasco DW, Martinez D, Wood DL, et al. Safety and activity of DCR-MYC, a first-in-class Dicer-substrate small interfering RNA (DsiRNA) targeting MYC, in a phase I study in patients with advanced solid tumors. J Clin Oncol. 2015;33(15_suppl):11006.
Safety Study of a Cell Penetrating Peptide (p28) to Treat Solid Tumors That Resist Standard Methods of Treatment [Available from: https://ClinicalTrials.gov/show/NCT00914914.
p28 in Treating Younger Patients With Recurrent or Progressive Central Nervous System Tumors [Available from: https://ClinicalTrials.gov/show/NCT01975116.
Lulla RR, Goldman S, Beattie C, Yamada T, Pollack I, Fisher PG, et al. Phase 1 trial of p28 (NSC745104), a non-HDM2 mediated peptide inhibitor of p53 ubiquitination in children with recurrent or progressive CNS tumors: a final report from the Pediatric Brain Tumor Consortium. J Clin Oncol. 2015;33(15_suppl):10059.
Warso MA, Richards JM, Mehta D, Christov K, Schaeffer C, Rae Bressler L, et al. A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours. Br J Cancer. 2013;108(5):1061–70.
Senevirathne SA, Washington KE, Biewer MC, Stefan MC. PEG based anti-cancer drug conjugated prodrug micelles for the delivery of anti-cancer agents. J Mater Chem B. 2016;4(3):360–70.
Li W, Zhan P, De Clercq E, Lou H, Liu X. Current drug research on PEGylation with small molecular agents. Prog Polym Sci. 2013;38(3):421–44.
C-f X, Wang J. Delivery systems for siRNA drug development in cancer therapy. Asian J Pharm Sci. 2015;10(1):1–12.
Anselmo AC, Mitragotri S. Nanoparticles in the clinic. Bioeng Transl Med. 2016;1(1):10–29.
Zuckerman JE, Davis ME. Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat Rev Drug Discov. 2015;14(12):843–56.
Tatiparti K, Sau S, Kashaw SK, Iyer AK. siRNA delivery strategies: a comprehensive review of recent developments. Nanomaterials (Basel). 2017;7(4).
Stern JM, Kibanov Solomonov VV, Sazykina E, Schwartz JA, Gad SC, Goodrich GP. Initial evaluation of the safety of nanoshell-directed photothermal therapy in the treatment of prostate disease. Int J Toxicol. 2016;35(1):38–46.
Guidotti G, Brambilla L, Rossi D. Cell-penetrating peptides: from basic research to clinics. Trends Pharmacol Sci. 2017;38(4):406–24.
Charlesworth CT, Deshpande PS, Dever DP, Dejene B, Gomez-Ospina N, Mantri S, et al. Identification of pre-existing adaptive immunity to Cas9 proteins in humans. bioRxiv. 2018.
Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol. 2018;36(8):765–71.
Funding
B. E. G. acknowledges fellowship support from the Alfred P. Sloan Foundation, the University of Iowa Graduate College, and the National GEM Consortium. E. J. Devor acknowledges support from the University of Iowa Department of Obstetrics and Gynecology Research Development Fund. A.K.S. acknowledges support from the National Cancer Institute at the National Institutes of Health (5P30CA086862) and the Lyle and Sharon Bighley Chair of Pharmaceutical Sciences.
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Givens, B.E., Naguib, Y.W., Geary, S.M. et al. Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Therapeutics. AAPS J 20, 108 (2018). https://doi.org/10.1208/s12248-018-0267-9
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DOI: https://doi.org/10.1208/s12248-018-0267-9