Recent advances in development of nano-carriers for immunogene therapy in various complex disorders

Document Type : Review Article

Authors

1 Immunology Department, Faculty of Medicine, Golestan University of Medical Science, Gorgan, Iran

2 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Advanced Sciences and Technologies, North Khorasan University of Medical Sciences, Bojnurd, Iran

4 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA

5 Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad, University of Medical Sciences, Mashhad, Iran

Abstract

Immunotherapy is a novel preference for the treatment of various complex diseases. Considering the application of varying agents for suppression or activation of the immune system, immunogene therapy was confirmed to stand as a proper alternative for other immunotherapeutic strategies due to its capability in targeting cells with more specificity that leads to controlling the expression of therapeutic genes. This method facilitates the local and single-dose application of most gene therapies that result in the usage of high therapeutic doses with a low risk of systemic side effects while being cost-efficient in long-term administrations. However, the existing barriers between the administration site and cell nucleus limited the clinical uses of genetic materials. These challenges can be overcome through the promising method of exerting non-carriers with high stability, low toxicity/immunogenicity, and simple modifications. In this study, we attempted to review the potential of nanoparticle application throughout the immunogene therapy of different diseases including cancer, microbial diseases, allergies, inflammatory bowel disease, rheumatoid arthritis, and respiratory infections. We included the outline of some challenges and opportunities in regards to the delivery of genetic materials that are based on nano-systems through immunotherapy of these disorders. Next to the promising future of these vectors, more detailed analyses are required to overcome the current limitations in clinical approaches.

Keywords


1. Pusuluri A, Wu D, Mitragotri S. Immunological consequences of chemotherapy: Single drugs, combination therapies and nanoparticle-based treatments. J Control Release 2019;305:130-154.
2. Smith AJ, Oertle J, Prato D. Immunotherapy in cancer treatment. Open J Med Microbiol 2014;4:178.
3. Oroojalian F, Charbgoo F, Hashemi M, Amani A, Yazdian-Robati R, Mokhtarzadeh A, et al. Recent advances in nanotechnology-based drug delivery systems for the kidney. J Control Release  2020;321:442-462.
4. Naldini L. Gene Therapy Returns to Centre Stage 2015;526:351-360.
5. Zhou Y, Zhang C, Liang W. Development of RNAi technology for targeted therapy—a track of siRNA based agents to RNAi therapeutics. J Control Release 2014;193:270-281.
6. Zhang X, Godbey W. Viral vectors for gene delivery in tissue engineering. Adv Drug Deliv Rev 2006;58:515-534.
7. Cherkassky L, Grosser R, Adusumilli PS. Regional Gene Therapy for Cancer.  J Cancer Ther 2020;55-71.
8. Heilbronn R, Weger S. Viral vectors for gene transfer: current status of gene therapeutics.  Drug Deliv.2010;143-170.
9. Fischer A, Hacein-Bey-Abina S. Gene therapy for severe combined immunodeficiencies and beyond. Exp Med 2020;217:e20190607.
10. Ugwu GC, Egbuji JVI, Okanya LC, Omeje JN, Eyo JE. Gene therapy, physiological applications, problems and prospects-a review. Anim Res Int 2019;16:3367-3392.
11. Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet 2020;21:255-272.
12. Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune Immune responses to viral gene therapy vectors. Mol Ther 2020;28:709-722.
13. Deng W, Fu M, Cao Y, Cao X, Wang M, Yang Y, et al. Angelica sinensis polysaccharide nanoparticles as novel non-viral carriers for gene delivery to mesenchymal stem cells. Nanomed: Nanotechnol Biol Med 2013;9:1181-1191.
14. Kommareddy S, Amiji M. Poly(ethylene glycol)–modified thiolated gelatin nanoparticles for glutathione-responsive intracellular DNA delivery. Nanomed: Nanotechnol Biol Med 2007;3:32-42.
15. Pathak A, Patnaik S, Gupta KC. Recent trends in non-viral vector-mediated gene delivery. Biotechnol J 2009;4:1559-1572.
16. Chuan D, Jin T, Fan R, Zhou L, Guo G. Chitosan for gene delivery: Methods for improvement and applications. Adv Colloid Interface Sci 2019;268:25-38.
17. Pridgen EM, Langer R, Farokhzad OC. Biodegradable, polymeric nanoparticle delivery systems for cancer therapy. Nanomedicine 2007;2:669-680.
18. Ozpolat B, Sood A, Lopez‐Berestein G. Nanomedicine based approaches for the delivery of siRNA in cancer. J Intern Med 2010;267:44-53.
19. Bayat S, Rabbani Zabihi A, Amel Farzad S, Movaffagh J, Hashemi E, Arabzadeh S, Hahsemi M. Evaluation of debridement effects of bromelain-loaded sodium alginate nanoparticles incorporated into chitosan hydrogel in animal models. Iran J Basic Med Sci 2021; 24:1404-1412. 
20. Rezaei M, Hosseini SN, Khavari-Nejad RA, Najafi F, Mahdavi M. Fast antibody responses by immuno-targeting and nanotechnology strategies versus HBsAg vaccine. Iran J Basic Med Sci 2021; 24:545-555.
21. Fontana F, Liu D, Hirvonen J, Santos HA. Delivery of therapeutics with nanoparticles: what’s new in cancer immunotherapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2017;9:e1421.
22. Rashidi A, Omidi M, Choolaei M, Nazarzadeh M, Yadegari A, Haghierosadat F, et al., editors. Electromechanical properties of vertically aligned carbon nanotube. Adv Mat Res 2013;332-336.
23. Singh MS, Bhaskar S. Nanocarrier-based immunotherapy in cancer management and research. ImmunoTargets and Therapy 2014;3:121-134.
24. Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 2004;4:249.
25. Fu J, Cai J, Ling G, Li A, Zhao J, Guo X, et al. Cationic polymers for enhancing CpG oligodeoxynucleotides-mediated cancer immunotherapy. Eur 2019;113:115-132.
26. De Jong S, Chikh G, Sekirov L, Raney S, Semple S, Klimuk S, et al. Encapsulation in liposomal nanoparticles enhances the immunostimulatory, adjuvant and anti-tumor activity of subcutaneously administered CpG ODN. Cancer Immunol Immunother 2007;56:1251-1264.
27. Gao Q, Hong J, Xiao X, Cao H, Yuan R, Liu Z, et al. T cell epitope of arginine kinase with CpG co-encapsulated nanoparticles attenuates a shrimp allergen-induced Th2-bias food allergy. Biosci Biotechnol Biochem 2019;84:804-814.
28. Gunawardana T, Ahmed KA, Goonewardene K, Popowich S, Kurukulasuriya S, Karunarathana R, et al. CpG-ODN induces a dose-dependent enrichment of immunological niches in the spleen and lungs of neonatal chicks that correlates with the protectivei mmunity against Escherichia coli. J Immunol Res      2020; 2020:2704728.
29. Jahanban‐Esfahlan R, Seidi K, Majidinia M, Karimian A, Yousefi B, Nabavi SM, et al. Toll‐like receptors as novel therapeutic targets for herpes simplex virus infection. Rev Med Virol 2019;29:e2048.
30. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709-760.
31. Mavi SA, Modarressi MH, Mohebali M, Shojaee S, Zeraati H, al. e. Assessment of the immunogenicity and protective efficiency of a novel dual-promoter DNA vaccine, harboring SAG1 and GRA7 genes, from RH strain of Toxoplasma gondii in BALB/c mice. Infect Drug Resist 2019;12:2519.
32. Yang Y, Chen J, Li H, Wang Y, Xie Z, Wu M, et al. Porcine interleukin-2 gene encapsulated in chitosan nanoparticles enhances immune response of mice to piglet paratyphoid vaccine. Comp Immunol Microbiol Infect Dis 2007;30:19-32.
33. Bourquin C, Anz D, Zwiorek K, Lanz AL, Fuchs S, Weigel S, et al. Targeting CpG oligonucleotides to the lymph node by nanoparticles elicits efficient antitumoral immunity. J Immunol. 2008;181:2990-2998.
34. Kawakami S, Higuchi Y, Hashida M. Nonviral approaches for targeted delivery of plasmid DNA and oligonucleotide. J Pharm Sci. 2008;97:726-745.
35. Xu Y, Yuen P-W, Lam J. Intranasal DNA vaccine for protection against respiratory infectious diseases: the delivery perspectives. Pharmaceutics. 2014;6:378-415.
36. Pishdadian A, Varasteh A, Gholamin M, Roozbeh Nasiraie L, Hosseinpour M, Moghadam M, Sankian M, Lung‐derived innate cytokines: New epigenetic targets of allergen‐specific sublingual immunotherapy. Iran J Basic Med Sci 2016; 19:64‐71. 
37. Havenar-Daughton C, Carnathan DG, Boopathy AV, Upadhyay AA, Murrell B, Reiss SM, et al. Rapid germinal center and antibody responses in non-human primates after a single nanoparticle vaccinei mmunization. Cell Rep 2019;29:1756-1766. e1758.
38. Liu MA. A comparison of plasmid DNA and mrna as vaccine technologies. Vaccines 2019;7:37-57.
39. Gupta J, Pathak M, Misra S, Misra-Bhattacharya S. CpG enhances the immunogenicity of heterologous DNA-prime/protein-boost vaccination with the heavy chain myosin of Brugia malayi in BALB/c mice. Parasitol Res 2019;118:1943-1952.
40. Wu H-M, Xie Q-M, Zhao C-C, Xu J, Fan X-Y, Fei G-H. Melatonin biosynthesis restored by CpG oligodeoxynucleotides attenuates allergic airway inflammation via regulating NLRP3 inflammasome. Life Sci 2019;239:117067.
41. Chew JL, Wolfowicz CB, Mao H-Q, Leong KW, Chua KY. Chitosan nanoparticles containing plasmid DNA encoding house dust mite allergen, Der p 1 for oral vaccination in mice. Vaccine 2003;21:2720-2729.
42. Kumar M, Kong X, Behera AK, Hellermann GR, Lockey RF, Mohapatra SS. Chitosan IFN-γ-pDNA nanoparticle (CIN) therapy for allergic asthma. Genet Vaccines Ther 2003;1:3-13.
43. Hou Z, Han Q, Zhang C, Zhang J. Perspectives on RNA Interference in Immunopharmacology and Immunotherapy. J RNAi Gene Silenc 2016:285-309.
44. Kawasaki H, Taira K. Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 2004;431:211.
45. Morris KV, Chan SW-L, Jacobsen SE, Looney DJ. Small interfering RNA-induced transcriptional gene silencing in human cells. Science 2004;305:1289-1292.
46. Bowers K. RNA interference-mediated inhibition of ESCRT in mammalian cells.  The ESCRT Complexes 2019;1998:305-318.
47. Lichtenberg SS, Tsyusko OV, Palli SR, Unrine JM. Uptake and bioactivity of chitosan/double-stranded RNA polyplex nanoparticles in Caenorhabditis elegans. Environ Sci Technol 2019;53:3832-3840.
48. Mansoori B, Mohammadi A, Shir Jang S, Baradaran B. Mechanisms of immune system activation in mammalians by small interfering RNA (siRNA). Artif Cells Nanomed Biotechnol 2016;44:1589-1596.
49. Wittrup A, Lieberman J. Knocking down disease: a progress report on siRNA therapeutics. Nat Rev Genet 2015;16:543-552.
50. Cubillos-Ruiz JR, Engle X, Scarlett UK, Martinez D, Barber A, Elgueta R, et al. Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest 2009;119:2231-2244.
51. Teo PY, Yang C, Whilding LM, Parente-Pereira AC, Maher J, George AJ, et al. Ovarian cancer immunotherapy using PD-L1 siRNA targeted delivery from folic acid-functionalized polyethylenimine: strategies to enhance T cell killing. Adv Healthc Mater 2015;4:1180-1189.
52. Jerome V, Graser A, Muller R, Kontermann RE, Konur A. Cytotoxic T lymphocytes responding to low dose TRP2 antigen are induced against B16 melanoma by liposome-encapsulated TRP2 peptide and CpG DNA adjuvant. J Immunother. 2006;29:294-305.
53. Xu Z, Ramishetti S, Tseng Y-C, Guo S, Wang Y, Huang L. Multifunctional nanoparticles co-delivering Trp2 peptide and CpG adjuvant induce potent cytotoxic T-lymphocyte response against melanoma and its lung metastasis. J Control Release  2013;172:259-265.
54. Ito A, Matsuoka F, Honda H, Kobayashi T. Heat shock protein 70 gene therapy combined with hyperthermia using magnetic nanoparticles. Cancer Gene Ther 2003;10:918-925.
55. Oberli MA, Reichmuth AM, Dorkin JR, Mitchell MJ, Fenton OS, Jaklenec A, et al. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett 2017;17:1326-1335.
56. Yan S, Rolfe BE, Zhang B, Mohammed YH, Gu W, Xu ZP. Polarized immune responses modulated by layered double hydroxides nanoparticle conjugated with CpG. Biomaterials 2014;35:9508-9516.
57. Hobo W, Novobrantseva TI, Fredrix H, Wong J, Milstein S, Epstein-Barash H, et al. Improving dendritic cell vaccine immunogenicity by silencing PD-1 ligands using siRNA-lipid nanoparticles combined with antigen mRNA electroporation. Cancer Immunol Immunother 2013;62:285-297.
58. Chellat F, Grandjean-Laquerriere A, Le Naour R, Fernandes J, Yahia L, Guenounou M, et al. Metalloproteinase and cytokine production by THP-1 macrophages following exposure to chitosan-DNA nanoparticles. Biomaterials 2005;26:961-970.
59. Kim TH, Nah JW, Cho MH, Park TG, Cho CS. Receptor-mediated gene delivery into antigen presenting cells using mannosylated chitosan/DNA nanoparticles. J Nanosci Nanotechnol 2006;6:2796-2803.
60. Li Y, Su Z, Zhao W, Zhang X, Momin N, Zhang C, et al. Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nat Rev Cancer 2020;1:882-893.
61. Cubillos-Ruiz JR, Baird JR, Tesone AJ, Rutkowski MR, Scarlett UK, Camposeco-Jacobs AL, et al. Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. Cancer Res 2012;72:1683-1693.
62. Suzuki R, Namai E, Oda Y, Nishiie N, Otake S, Koshima R, et al. Cancer gene therapy by IL-12 gene delivery using liposomal bubbles and tumoral ultrasound exposure. J Control Release 2010;142:245-250.
63. Conde J, Bao C, Tan Y, Cui D, Edelman ER, Azevedo HS, et al. Dual targeted immunotherapy via in vivo delivery of biohybrid RNAi-peptide nanoparticles to tumor-associated macrophages and cancer cells. Adv Funct Mater 2015;25:4183-4194.
64. Rodrigo-Garzon M, Berraondo P, Ochoa L, Zulueta JJ, Gonzalez-Aseguinolaza G. Antitumoral efficacy of DNA nanoparticles in murine models of lung cancer and pulmonary metastasis. Cancer Gene Ther 2010;17:20-27.
65. Sun Y, Yang J, Yang T, Li Y, Zhu R, Hou Y, et al. Co-delivery of IL-12 cytokine gene and cisplatin prodrug by a polymetformin-conjugated nanosystem for lung cancer chemo-gene treatment through chemotherapy sensitization and tumor microenvironment modulation. Acta Biomater. 2021;128:447-461.
66. Diez S, Navarro G, de ICT. In vivo targeted gene delivery by cationic nanoparticles for treatment of hepatocellular carcinoma. J Gene Med 2009;11:38-45.
67. Huang K-W, Hsu F-F, Qiu JT, Chern G-J, Lee Y-A, Chang C-C, et al. Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer. Sci Adv 2020;6:eaax5032.
68. Azimifar MA, Salmasi Z, Doosti A, Babaei N, Hashemi M. Evaluation of the efficiency of modified PAMAM dendrimer with low molecular weight protamine peptide to deliver IL‐12 plasmid into stem cells as cancer therapy vehicles. Biotechnol Prog. 2021;37:e3175.
69. Zhao X, Li F, Li Y, Wang H, Ren H, Chen J, et al. Co-delivery of HIF1alpha siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer. Biomaterials 2015;46:13-25.
70. Men K, Huang R, Zhang X, Zhang R, Zhang Y, He M, et al. Local and systemic delivery of interleukin-12 gene by cationic micelles for cancer immunogene therapy. J Biomed Nanotech 2018;14:1719-1730.
71. Pishavar E, Oroojalian F, Ramezani M, Hashemi M. Cholesterol‐conjugated PEGylated PAMAM as an efficient nanocarrier for plasmid encoding interleukin‐12 immunogene delivery toward colon cancer cells.     Biotechnol Prog 2020;36:e2952.
72. Liu X, Wang B, Li Y, Hu Y, Li X, Yu T, et al. Powerful anticolon tumor effect of targeted gene immunotherapy using folate-modified nanoparticle delivery of CCL19 to activate the immune system. ACS Cent Sci. 2019;5:277-289.
73. Lei S, Zhang X, Men K, Gao Y, Yang X, Wu S, et al. Efficient colorectal cancer gene therapy with IL-15 mRNA nanoformulation. Mol Pharm. 2020;17:3378-3391.
74. Schneider T, Becker A, Ringe K, Reinhold A, Firsching R, Sabel BA. Brain tumor therapy by combined vaccination and antisense oligonucleotide delivery with nanoparticles. J Neuroimmunol 2008;195:21-27.
75. Zoller M, Strubel A, Hammerling G, Andrighetto G, Raz A, Ben-Ze’ev A. Interferon-gamma treatment of B16 melanoma cells: opposing effects for non-adaptive and adaptive immune defense and its reflection by metastatic spread. Int J Cancer. 1988;41:256-266.
76. Melief CJ. Tumor eradication by adoptive transfer of cytotoxic T lymphocytes. Adv Cancer Res. 1992;58:143-175.
77. Melief CJ, Van Der Burg SH, Toes RE, Ossendorp F, Offringa R. Effective therapeutic anticancer vaccines based on precision guiding of cytolytic T lymphocytes. Immunol Rev. 2002;188:177-182.
78. Hulina-Tomašković A, Somborac-Bačura A, Rajković MG, Bosnar M, Samaržija M, Rumora L. Effects of extracellular Hsp70 and cigarette smoke on differentiated THP-1 cells and human monocyte-derived macrophages.     Mol Immunol. 2019;111:53-63.
79. Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006;13:816-825.
80. Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, et al. PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res. 2013;19:1363-1374.
81. Duraiswamy J, Freeman GJ, Coukos G. Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 2013;73:6900-6912.
82. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104:3360-3365.
83. Maine CJ, Aziz NH, Chatterjee J, Hayford C, Brewig N, Whilding L, et al. Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer.     Cancer Immunol Immunother. 2014;63:215-224.
84. Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, Liu G, et al. MiR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell. 2007;129:147-161.
85. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316:608-611.
86. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604-608.
87. O’Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205:5855-5894.
88. O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104:1604-1609.
89. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71-78.
90. Cook J, Hagemann T. Tumour-associated macrophages and cancer. Curr Opin Pharmacol. 2013;13:595-601.
91. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. 2011;144:646-674.
92. Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol. 2012;13:722-728.
93. Roupakia E, Markopoulos GS, Kolettas E. IL-12-mediated transcriptional regulation of matrix metalloproteinases. Biosci Rep. 2018;38: BSR20171420.
94. Luongo M, Brigida AL, Mascolo L, Gaudino G. Possible therapeutic effects of ozone mixture on hypoxia in tumor development. Anticancer Res. 2017;37:425-435.
95. Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol. 2011;29:1005-1010.
96. Hu Y-L, Miao P-H, Huang B, Zhang T-Y, Hu Z-J, Tabata Y, et al. Reversal of tumor growth by gene modification of mesenchymal stem cells using spermine-pullulan/DNA nanoparticles. J Biomed Nanotech. 2014;10:299-308.
97. Xu J, Dai W, Wang Z, Chen B, Li Z, Fan X. Intranasal vaccination with chitosan-DNA nanoparticles expressing pneumococcal surface antigen a protects mice against nasopharyngeal colonization by Streptococcus pneumoniae. Clin Vaccine Immunol. 2011;18:75-81.
98. Dolina JS, Sung SS, Novobrantseva TI, Nguyen TM, Hahn YS. Lipidoid nanoparticles containing PD-L1 siRNA delivered in vivo enter kupffer cells and enhance NK and CD8(+) T Cell-mediated hepatic antiviral immunity. Mol Ther Nucleic Acids. 2013;2:e72.
99. Bivas-Benita M, van Meijgaarden KE, Franken KL, Junginger HE, Borchard G, Ottenhoff TH, et al. Pulmonary delivery of chitosan-DNA nanoparticles enhances the immunogenicity of a DNA vaccine encoding HLA-A*0201-restricted T-cell epitopes of Mycobacterium tuberculosis. Vaccine. 2004;22:1609-1615.
100. Zhang W, Yang H, Kong X, Mohapatra S, San Juan-Vergara H, Hellermann G, et al. Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene. Nat Med. 2005;11:56-62.
101. Kumar M, Behera AK, Lockey RF, Zhang J, Bhullar G, de la Cruz CP, et al. Intranasal gene transfer by chitosan–DNA nanospheres protects BALB/c mice against acute respiratory syncytial virus infection. Hum Gene Ther. 2002;13:1415-1425.
102. Spolski R, Li P, Leonard WJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018;18:648-659.
103. Morrison KE, Lake D, Crook J, Carlone GM, Ades E, Facklam R, et al. Confirmation of psaA in all 90 serotypes of Streptococcus pneumoniae by PCR and potential of this assay for identification and diagnosis. J Clin Microbiol. 2000;38:434-437.
104. Curtis MM, Way SS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology. 2009;126:177-185.
105. Zhang Z, Clarke TB, Weiser JN. Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Invest. 2009;119:1899-1909.
106.    Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med. 2003;198:39-50.
107. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A. 2003;100:5336-5341.
108. Lechmann M, Krooshoop DJ, Dudziak D, Kremmer E, Kuhnt C, Figdor CG, et al. The extracellular domain of CD83 inhibits dendritic cell-mediated T cell stimulation and binds to a ligand on dendritic cells. J Exp Med. 2001;194:1813-1821.
109. Abreo A, Wu P, Donovan BM, Ding T, Gebretsadik T, Huang X, et al. Infant respiratory syncytial virus bronchiolitis and subsequent risk of pneumonia, otitis media, and antibiotic utilization. Clin Infect Dis. 2019;71:211-214.
110. Li X, Sambhara S, Li CX, Ettorre L, Switzer I, Cates G, et al. Plasmid DNA encoding the respiratory syncytial virus G protein is a promising vaccine candidate. Virology. 2000;269:54-65.
111. Murphy BR, Collins PL. Live-attenuated virus vaccines for respiratory syncytial and parainfluenza viruses: applications of reverse genetics. J Clin Investig 2002;110:21-27.
112. Schwarz B, Morabito KM, Ruckwardt TJ, Patterson DP, Avera J, Miettinen HM, et al. Viruslike particles encapsidating respiratory syncytial virus M and M2 proteins induce robust T cell responses. ACS Biomater Sci Eng 2016;2:2324-2332.
113. Song X, Xiao H-T, Liao C-H, Li L, Kang Q-R, Jiang Y-C, et al. Natural products: the master regulators of antiviral cytokines. Curr Org Chem 2017;21:1805-1823.
114. Kay AB. Allergy and allergic diseases. NEJM. 2001;344:30-37.
115. Li G, Liu Z, Liao B, Zhong N. Induction of Th1-type immune response by chitosan nanoparticles containing plasmid DNA encoding house dust mite allergen Der p 2 for oral vaccination in mice. Cell Mol Immunol 2009;6:45-50.
116. Roy K, Mao H-Q, Huang S-K, Leong KW. Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 1999;5:387-391.
117. Da Silva AL, de Oliveira GP, Kim N, Cruz FF, Kitoko JZ, Blanco NG, et al. Nanoparticle-based thymulin gene therapy therapeutically reverses key pathology of experimental allergic asthma. Sci Adv 2020;6:eaay7973.
118. Tang C, Inman MD, van Rooijen N, Yang P, Shen H, Matsumoto K, et al. Th type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-γ-dependent mechanism. J Immunol 2001;166:1471-1481.
119. Hajavi J, Hashemi M, Sankian M. Evaluation of size and dose effects of rChe a 3 allergen loaded PLGA nanoparticles on modulation of Th2 immune responses by sublingual immunotherapy in mouse model of rhinitis allergic. Int J Pharm 2019;563:282-292.
120. Lehrer RI, Ganz T. Biochemistry and function of monocytes and macrophages. Hematol 2001;6:865-869.
121. Da Silva AL, Martini SV, Abreu SC, Samary CdS, Diaz BL, Fernezlian S, et al. DNA nanoparticle-mediated thymulin gene therapy prevents airway remodeling in experimental allergic asthma. J Control Release 2014;180:125-133.
122. Isgro M, Bianchetti L, Marini M, Bellini A, Schmidt M, Mattoli S. The CC motif chemokine ligands CCL5, CCL11, and CCL24 induce the migration of circulating fibrocytes from patients with severe asthma. Mucosal Immunol 2013;6:718-727.
123. Lloyd CM, Hawrylowicz CM. Regulatory T cells in asthma. Immunity 2009;31:438-449.
124. Isaacs KL, Lewis JD, Sandborn WJ, Sands BE, Targan SR. State of the art: IBD therapy and clinical trials in IBD. Inflamm Bowel Dis 2005;11:S3-S12.
125. Korzenik JR, Podolsky DK. Evolving knowledge and therapy of inflammatory bowel disease. Nat Rev Drug Discov 2006;5:197-209.
126. Kriegel C, Amiji M. Oral TNF-α gene silencing using a polymeric microsphere-based delivery system for the treatment of inflammatory bowel disease. J Control Release 2011;150:77-86.
127. Bhavsar M, Amiji M. Oral IL-10 gene delivery in a microsphere-based formulation for local transfection and therapeutic efficacy in inflammatory bowel disease. Gene Ther 2008;15:1200-1209.
128. Laroui H, Theiss AL, Yan Y, Dalmasso G, Nguyen HT, Sitaraman SV, et al. Functional TNFα gene silencing mediated by polyethyleneimine/TNFα siRNA nanocomplexes in inflamed colon. Biomaterials 2011;32:1218-1228.
129. Xiao B, Chen Q, Zhang Z, Wang L, Kang Y, Denning T, et al. TNFα gene silencing mediated by orally targeted nanoparticles combined with interleukin-22 for synergistic combination therapy of ulcerative colitis. J Control Release  2018;287:235-246.
130. Mueller C. Tumour necrosis factor in mouse models of chronic intestinal inflammation. Immunology. 2002;105:1-8.
131. Arend WP. Physiology of cytokine pathways in rheumatoid arthritis. Arthritis Rheumatol 2001;45:101-106.
132. Park S, Le TT, Slejko JF, Villalonga-Olives E, Onukwugha E. Changes in opioid utilization following tumor necrosis factor inhibitor initiation in patients with rheumatoid arthritis. Rheumatol Ther 2019;6:611-616.
133. Kumar R, Dammai V, Yadava P, Kleinau S. Gene targeting by ribozyme against TNF-α mRNA inhibits autoimmune arthritis. Gene Ther. 2005;12:1486-1493.
134. Schiffelers RM, Xu J, Storm G, Woodle MC, Scaria PV. Effects of treatment with small interfering RNA on joint inflammation in mice with collagen‐induced arthritis. Arthritis Rheumatol 2005;52:1314-1318.
135. Howard KA, Paludan SR, Behlke MA, Besenbacher F, Deleuran B, Kjems J. Chitosan/siRNA nanoparticle–mediated TNF-α knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model. Mol Ther. 2009;17:162-168.
136. Khoury M, Louis‐Plence P, Escriou V, Noel D, Largeau C, Cantos C, et al. Efficient new cationic liposome formulation for systemic delivery of small interfering RNA silencing tumor necrosis factor α in experimental arthritis. Arthritis Rheumatol 2006;54:1867-1877.
137. Nissler K, Pohlers D, Hückel M, Simon J, Bräuer R, Kinne R. Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen induced arthritis: influence on macrophage activation. ARD 2004;63:1470-1477.
138. Genprex Announces Initiation of its Phase 1/2 Acclaim-1 Clinical Trial for REQORSA™ Immunogene Therapy in Combination with Tagrisso® to Treat Non-Small Cell Lung Cancer Following FDA Review Yahoo finance2021 [Available from: https://finance.yahoo.com/news/genprex-announces-initiation-phase-1-123000637].
139. Malmström P-U, Loskog AS, Lindqvist CA, Mangsbo SM, Fransson M, Wanders A, et al. AdCD40L immunogene therapy for bladder carcinoma—the first phase I/IIa trial.     Clin Cancer Res 2010;16:3279-3287.
140. Tristán-Manzano M, Justicia-Lirio P, Maldonado-Pérez N, Cortijo-Gutiérrez M, Benabdellah K, Martin F. Externally-controlled systems for immunotherapy: from bench to bedside. Front immunol 2020;11:2044-2061.
141. Xu J, Melenhorst JJ, Fraietta JA. Toward precision manufacturing of immunogene T-cell therapies. Cytotherapy 2018;20:623-638.