Nanovaccines pp 105-130 | Cite as

Silica-Based Mucosal Nanovaccines

  • Sergio Rosales-Mendoza
  • Omar González-Ortega


The use of nanocarriers to enhance the immunogenicity of subunit vaccines is acquiring relevance in the vaccinology field. Silica-based nanomaterials have attractive characteristics for this application since they are biodegradable and biocompatible, can be easily conjugated with antigens and adjuvants, and exert immunostimulatory effects. The latter effects derive from the facts that silica nanoparticles are efficiently taken up by antigen presenting cells and induce inflammatory responses, able to traffic to lymph nodes, and proper delivery vehicles of some adjuvants such as CpG oligonucleotides. Herein, the synthesis and functionalization approaches for silica nanoparticles are presented and current developments on new vaccines based on them are analyzed. The preclinical analysis of silica-based nanovaccines reveals promising findings in vaccination models against infectious diseases (bacterial and viral) affecting humans and animals. Perspectives for the field are identified, which essentially contemplate the need of performing clinical trials, completing toxicity assessment, expanding the application to non-communicable diseases, and starting the development of multiepitope vaccines.


Hepatitis B Enterohemorrhagic Escherichia coli Bioconjugation Influenza Newcastle disease 


  1. Ajitha S, Sugunan S (2010) Tuning mesoporous molecular sieve SBA-15 for the immobilization of α-amylase. J Porous Mater 17(3):341–349CrossRefGoogle Scholar
  2. An M, Li M, Xi J, Liu H (2017) Silica nanoparticle as a lymph node targeting platform for vaccine delivery. ACS Appl Mater Interfaces 9(28):23466–23475CrossRefGoogle Scholar
  3. Artaki F, Bradley M, Zerda TW, Jonas J (1985) NMR and Raman study of the hydrolysis reaction in sol-gel processes. J Phys Chem 89:4399–4404CrossRefGoogle Scholar
  4. Autefage H, Briand-Mésange F, Cazalbou S, Drouet C, Fourmy D, Gonçalvès S, Salles J, Combes C, Swider P, Rey C (2009) Adsorption and release of BMP-2 on nanocrystalline apatite-coated and uncoated hydroxyapatite/β-tricalcium phosphate porous ceramics. J Biomed Mater Res 91B:706–715CrossRefGoogle Scholar
  5. Bogush GH, Tracy MA, Zukoski CF (1988) Preparation of monodisperse silica particles: control of size and mass fraction. J Non-Cryst Solids 104:95–106CrossRefGoogle Scholar
  6. Caruso F, Caruso R, Mohwald H (1998) Nanoengineering of inorganic and hybrid hollow spheres by colloidal templating. Science (New York, NY) 282:1111–1114CrossRefGoogle Scholar
  7. Carvalho LV, Ruiz Rde C, Scaramuzzi K, Marengo EB, Matos JR, Tambourgi DV, Fantini MC, Sant’Anna OA (2010) Immunological parameters related to the adjuvant effect of the ordered mesoporous silica SBA-15. Vaccine 28:7829–7836CrossRefGoogle Scholar
  8. Cha BG, Jeong JH, Kim J (2018) Extra-large pore mesoporous silica nanoparticles enabling co-delivery of high amounts of protein antigen and toll-like receptor 9 agonist for enhanced cancer vaccine efficacy. ACS Cent Sci 4(4):484–492CrossRefGoogle Scholar
  9. Chen S, Dong P, Yang G, Yang J (1996) Kinetics of formation of monodisperse colloidal silica particles through the hydrolysis and condensation of tetraethylorthosilicate. Ind Eng Chem Res 35:4487–4493CrossRefGoogle Scholar
  10. Chen X, Randall DP, Perruchot C, Watts JF, Patten TE, von Werne T, Armes SP (2003) Synthesis and aqueous solution properties of polyelectrolyte-grafted silica particles prepared by surface-initiated atom transfer radical polymerization. J Colloid Interface Sci 257(1):56–64CrossRefGoogle Scholar
  11. Chen Y, Chen H, Guo L, He Q, Chen F, Zhou J, Feng J, Shi J (2010) Hollow/rattle-type mesoporous nanostructures by a structural difference-based selective etching strategy. ACS Nano 4:529–539CrossRefGoogle Scholar
  12. Chen Y, Chen H-R, Shi J-L (2014) Construction of homogenous/heterogeneous hollow mesoporous silica nanostructures by silica-etching chemistry: principles, synthesis, and applications. Acc Chem Res 47:125–137CrossRefGoogle Scholar
  13. Chen YC, Smith T, Hicks RH, Doekhie A, Koumanov F, Wells SA, Edler KJ, van den Elsen J, Holman GD, Marchbank KJ, Sartbaeva A (2017) Thermal stability, storage and release of proteins with tailored fit in silica. Sci Rep 7:46568CrossRefGoogle Scholar
  14. Chou KS, Chen CC (2003) Preparation and characterization of monodispersed silica colloids. Adv Technol Mater Mater Process J 5:31–35Google Scholar
  15. Dellacherie MO, Li AW, Lu BY, Mooney DJ (2018) Covalent conjugation of peptide antigen to mesoporous silica rods to enhance cellular responses. Bioconjug Chem 29(3):733–741CrossRefGoogle Scholar
  16. Ding Y, Yin G, Liao X, Huang Z, Chen X, Yao Y, Li J (2013) A convenient route to synthesize SBA-15 rods with tunable pore length for lysozyme adsorption. Microporous Mesoporous Mater 170:45–51CrossRefGoogle Scholar
  17. Eickhoff CS, Blazevic A, Killoran EA, Morris MS, Hoft DF (2019) Induction of mycobacterial protective immunity by sublingual BCG vaccination. Vaccine 37(36):5364–5370CrossRefGoogle Scholar
  18. Foged C, Brodin B, Frokjaer S, Sundblad A (2005) Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int J Pharm 298:315–322CrossRefGoogle Scholar
  19. Ganar K, Das M, Sinha S, Kumar S (2014) Newcastle disease virus: current status and our understanding. Virus Res 184:71–81CrossRefGoogle Scholar
  20. García-Soto MJ, González-Ortega O (2016) Synthesis of silica-core gold nanoshells and some modifications/variations. Gold Bull 49(3–4):111–131CrossRefGoogle Scholar
  21. Gemeinhart RA, Luo D, Saltzman WM (2005) Cellular fate of a modular DNA delivery system mediated by silica nanoparticles. Biotechnol Prog 21:532–537CrossRefGoogle Scholar
  22. Gheibi Hayat SM, Darroudi M (2019) Nanovaccine: a novel approach in immunization. J Cell Physiol 234(8):12530–12536CrossRefGoogle Scholar
  23. Giret S, Wong Chi Man M, Carcel C (2015) Mesoporous-silica-functionalized nanoparticles for drug delivery. Chem Eur J 21(40):13850–13865CrossRefGoogle Scholar
  24. Gómez DM, Urcuqui-Inchima S, Hernandez JC (2017) Silica nanoparticles induce NLRP3 inflammasome activation in human primary immune cells. Innate Immun 23(8):697–708CrossRefGoogle Scholar
  25. Guo H, Idris NM, Zhang Y (2011) LRET-based biodetection of DNA release in live cells using surface-modified upconverting fluorescent nanoparticles. Langmuir 27(6):2854–2860CrossRefGoogle Scholar
  26. Guo H, Hao R, Qian H, Sun S, Sun D, Yin H, Liu Z, Liu X (2012) Upconversion nanoparticles modified with aminosilanes as carriers of DNA vaccine for foot-and-mouth disease. Appl Microbiol Biotechnol 95(5):1253–1263CrossRefGoogle Scholar
  27. Guzman J, Gates BC (2003) Supported molecular catalysts: metal complexes and clusters on oxides and zeolites. Dalton Trans 17:3303–3318CrossRefGoogle Scholar
  28. Hafner AM, Corthésy B, Merkle HP (2013) Particulate formulations for the delivery of poly(I:C) as vaccine adjuvant. Adv Drug Deliv Rev 65(10):1386–1399CrossRefGoogle Scholar
  29. Hajizade A, Salmanian AH, Amani J, Ebrahimi F, Arpanaei A (2018) EspA-loaded mesoporous silica nanoparticles can efficiently protect animal model against enterohaemorrhagic E. coli O157: H7. Artif Cells Nanomed Biotechnol 46(Suppl 3):S1067–S1075CrossRefGoogle Scholar
  30. Hudson SP, Padera RF, Langer R, Kohane DS (2008) The biocompatibility of mesoporous silicates. Biomaterials 29:4045–4055CrossRefGoogle Scholar
  31. Ibrahim IAM, Zikry AAF, Sharaf MA (2010) Preparation of spherical silica nanoparticles: Stober silica. J Am Sci 6:985–989Google Scholar
  32. Kim K, Kim J, Kim W (2002) Influence of reaction conditions on sol-precipitation process producing silicon oxide particles. Ceram Int 28:187–194CrossRefGoogle Scholar
  33. Kim SI, Pham TT, Lee JW, Roh SH (2010) Releasing properties of proteins on SBA-15 spherical nanoparticles functionalized with aminosilanes. J Nanosci Nanotechnol 10:3467–3472CrossRefGoogle Scholar
  34. Knežević NŽ, Durand J-O (2015) Large pore mesoporous silica nanomaterials for application in delivery of biomolecules. Nanoscale 7:2199–2209CrossRefGoogle Scholar
  35. Lee HM, Banini BA (2019) Updates on chronic HBV: current challenges and future goals. Curr Treat Options Gastroenterol 17(2):271–291CrossRefGoogle Scholar
  36. Li X, Wang X, Ito A, Sogo Y, Cheng K, Oyane A (2009) Effect of coprecipitation temperature on the properties and activity of fibroblast growth factor-2 apatite composite layer. Mater Sci Eng 29(1):216–221CrossRefGoogle Scholar
  37. Li X, Wang X, Sogo Y, Ohno T, Onuma K, Ito A (2013) Mesoporous silica-calcium phosphate-tuberculin purified protein derivative composites as an effective adjuvant for cancer immunotherapy. Adv Healthc Mater 2(6):863–871CrossRefGoogle Scholar
  38. Liberman A, Mendez N, Trogler WC, Kummel AC (2014) Synthesis and surface functionalization of silica nanoparticles for nanomedicine. Surf Sci Rep 69(2–3):132–158CrossRefGoogle Scholar
  39. Lincopan N, Santana MR, Faquim-Mauro E, da Costa MH, Carmona-Ribeiro AM (2009) Silica-based cationic bilayers as immunoadjuvants. BMC Biotechnol 9:5CrossRefGoogle Scholar
  40. Liu T, Liu H, Fu C, Li L, Chen D, Zhang Y, Tang F (2013) Silica nanorattle with enhanced protein loading: a potential vaccine adjuvant. J Colloid Interface Sci 400:168–174CrossRefGoogle Scholar
  41. Meissner J, Prause A, Di Tommaso C, Bharti B, Findenegg GH (2015) Protein immobilization in surface-functionalized SBA-15: predicting the uptake capacity from the pore structure. J Phys Chem C 119:2438–2446CrossRefGoogle Scholar
  42. Meng Q, Xiang S, Zhang K, Wang M, Bu X, Xue P, Liu L, Sun H, Yang B (2012) A facile two-step etching method to fabricate porous hollow silica particles. J Colloid Interface Sci 384:22–28CrossRefGoogle Scholar
  43. Mercuri LP, Carvalho LV, Lima FA, Quayle C, Fantini MC, Tanaka GS, Cabrera WH, Furtado MF, Tambourgi DV, Matos JDR, Jaroniec M (2006) Ordered mesoporous silica SBA-15: a new effective adjuvant to induce antibody response. Small 2(2):254–256CrossRefGoogle Scholar
  44. Mody KT, Popat A, Mahony D, Cavallaro AS, Yu C, Mitter N (2013) Mesoporous silica nanoparticles as antigen carriers and adjuvants for vaccine delivery. Nanoscale 5:5167–5179CrossRefGoogle Scholar
  45. Mody KT, Mahony D, Cavallaro AS, Stahr F, Qiao SZ, Mahony TJ, Mitter N (2014) Freeze-drying of ovalbumin loaded mesoporous silica nanoparticle vaccine formulation increases antigen stability under ambient conditions. Int J Pharm 465(1–2):325–332CrossRefGoogle Scholar
  46. Nagai Y, Shiraishi D, Tanaka Y, Nagasawa Y, Ohwada S, Shimauchi H, Aso H, Endo Y, Sugawara S (2015) Transportation of sublingual antigens across sublingual ductal epithelial cells to the ductal antigen-presenting cells in mice. Clin Exp Allergy 45(3):677–686CrossRefGoogle Scholar
  47. Narayan R, Nayak U, Raichur A, Garg S (2018) Mesoporous silica nanoparticles: a comprehensive review on synthesis and recent advances. Pharmaceutics 10:118CrossRefGoogle Scholar
  48. Navarro-Tovar G, Palestino G, Rosales-Mendoza S (2016) An overview on the role of silica-based materials in vaccine development. Expert Rev Vaccines 15(11):1449–1462CrossRefGoogle Scholar
  49. Neuhaus V, Schwarz K, Klee A, Seehase S, Förster C, Pfennig O, Jonigk D, Fieguth HG, Koch W, Warnecke G, Yusibov V (2013) Functional testing of an inhalable nanoparticle based influenza vaccine using a human precision cut lung slice technique. PLoS One 8(8):e71728CrossRefGoogle Scholar
  50. Neuhaus V, Chichester JA, Ebensen T, Schwarz K, Hartman CE, Shoji Y, Guzmán CA, Yusibov V, Sewald K, Braun A (2014) A new adjuvanted nanoparticle-based H1N1 influenza vaccine induced antigen-specific local mucosal and systemic immune responses after administration into the lung. Vaccine 32(26):3216–3222CrossRefGoogle Scholar
  51. Nishijima N, Hirai T, Misato K, Aoyama M, Kuroda E, Ishii KJ, Higashisaka K, Yoshioka Y, Tsutsumi Y (2017) Human scavenger receptor A1-mediated inflammatory response to silica particle exposure is size specific. Front Immunol 8:379CrossRefGoogle Scholar
  52. Osseo-Asare K, Arriagada F (1990) Preparation of SiO2 nanoparticles in a on-ionic reverse micellar system. J Colloids Surf 50:321–339CrossRefGoogle Scholar
  53. Ow H, Larson DR, Srivastava M, Baird BA, Webb WW, Wiesner U (2005) Bright and stable core-shell fluorescent silica nanoparticles. Nano Lett 5:113–117CrossRefGoogle Scholar
  54. Pniewski T, Milczarek M, Wojas-Turek J, Pajtasz-Piasecka E, Wietrzyk J, Czyż M (2018) Plant lyophilisate carrying S-HBsAg as an oral booster vaccine against HBV. Vaccine 36(41):6070–6076CrossRefGoogle Scholar
  55. Porter KR, Raviprakash K (2017) DNA vaccine delivery and improved immunogenicity. Curr Issues Mol Biol 22:129–138CrossRefGoogle Scholar
  56. Rasmussen MK, Kardjilov N, Oliveira CLP, Watts B, Villanova J, Botosso VF, Sant'Anna OA, Fantini MCA, Bordallo HN (2019) 3D visualisation of hepatitis B vaccine in the oral delivery vehicle SBA-15. Sci Rep 9(1):6106CrossRefGoogle Scholar
  57. Sabbaghi A, Miri SM, Keshavarz M, Zargar M, Ghaemi A (2019) Inactivation methods for whole influenza vaccine production. Rev Med Virol 23:e2074Google Scholar
  58. Saeedi P, Yazdanparast M, Behzadi E, Salmanian AH, Mousavi SL, Nazarian S, Amani J (2017) A review on strategies for decreasing E. coli O157:H7 risk in animals. Microb Pathog 103:186–195CrossRefGoogle Scholar
  59. Scaramuzzi K, Oliveira DC, Carvalho LV, Tambourgi DV, Tenório EC, Rizzi M, Mussalem J, Fantini MC, Botosso VF, Sant Anna OA (2011) Nanostructured SBA-15 silica as an adjuvant in immunizations with hepatitis B vaccine. Einstein (Sao Paulo) 9(4):436–441CrossRefGoogle Scholar
  60. Scaramuzzi K, Tanaka GD, Neto FM, Garcia PR, Gabrili JJ, Oliveira DC, Tambourgi DV, Mussalem JS, Paixão-Cavalcante D, D'Azeredo Orlando MT, Botosso VF, Oliveira CL, Fantini MC, Sant’Anna OA (2016) Nanostructured SBA-15 silica: an effective protective vehicle to oral hepatitis B vaccine immunization. Nanomedicine 12(8):2241–2250CrossRefGoogle Scholar
  61. Sharma RK, Sharma S, Dutta S, Zboril R, Gawande MB (2015) Silica-nanosphere-based organic–inorganic hybrid nanomaterials: synthesis, functionalization and applications in catalysis. Green Chem 17:3207–3230CrossRefGoogle Scholar
  62. Sharma B, McLeland CB, Potter TM, Stern ST, Adiseshaiah PP (2018) Assessing NLRP3 inflammasome activation by nanoparticles. Methods Mol Biol 1682:135–147CrossRefGoogle Scholar
  63. Shen J, Xu R, Mai J, Kim HC, Guo X, Qin G, Yang Y, Wolfram J, Mu C, Xia X, Gu J, Liu X, Mao ZW, Ferrari M, Shen H (2013) High capacity nanoporous silicon carrier for systemic delivery of gene silencing therapeutics. ACS Nano 7:9867–9880CrossRefGoogle Scholar
  64. Skrastina D, Petrovskis I, Lieknina I, Bogans J, Renhofa R, Ose V, Dishlers A, Dekhtyar Y, Pumpens P (2014) Silica nanoparticles as the adjuvant for the immunisation of mice using hepatitis B core virus-like particles. PLoS One 9(12):e114006CrossRefGoogle Scholar
  65. Smith DM, Simon JK, Baker JR (2013) Applications of nanotechnology for immunology. Nat Rev Immunol 13:592–605CrossRefGoogle Scholar
  66. Tao Z, Morrow MP, Asefa T, Sharma KK, Duncan C, Anan A, Penefsky HS, Goodisman J, Souid AK (2008) Mesoporous silica nanoparticles inhibit cellular respiration. Nano Lett 8:1517–1526CrossRefGoogle Scholar
  67. Thiele L, Rothen-Rutishauser B, Jilek S, Wunderli-Allenspach H, Merkle HP, Walter E (2001) Evaluation of particle uptake in human blood monocyte-derived cells in vitro. Does phagocytosis activity of dendritic cells measure up with macrophages? J Control Release 76:59–71CrossRefGoogle Scholar
  68. Trewyn BG, Whitman CM, Lin VS-Y (2004) Morphological control of room temperature ionic liquid templated mesoporous silica nanoparticles for controlled release of antibacterial agents. Nano Lett 4:2139–2143CrossRefGoogle Scholar
  69. Tsai CP, Chen CY, Hung Y, Chang FH, Mou CY (2009) Monoclonal antibody-functionalized mesoporous silica nanoparticles (MSN) for selective targeting breast cancer cells. J Mater Chem 19(32):5737–5743CrossRefGoogle Scholar
  70. van Blaaderen A, Vrij A (1993) Synthesis and characterization of monodisperse colloidal organo-silica spheres. J Colloid Interface Sci 156:1–18CrossRefGoogle Scholar
  71. van Blaaderen A, van Geest J, Vrij A (1992) Monodisperse colloidal silica spheres from tetraalkoxysilanes: particle formation and growth mechanism. J Colloid Interface Sci 154:481–501CrossRefGoogle Scholar
  72. Wang L, Wang K, Santra S, Zhao X, Hilliard LR, Smith JE, Wu Y, Tan W (2006) Watching silica nanoparticles glow in the biological world. Anal Chem 78:646–654CrossRefGoogle Scholar
  73. Wang T, Jiang H, Zhao Q, Wang S, Zou M, Cheng G (2012) Enhanced mucosal and systemic immune responses obtained by porous silica nanoparticles used as an oral vaccine adjuvant: effect of silica architecture on immunological properties. Int J Pharma 436:351–358CrossRefGoogle Scholar
  74. Wang X, Li X, Ito A, Sogo Y, Ohno T (2013) Particle-size-dependent toxicity and immunogenic activity of mesoporous silica-based adjuvants for tumor immunotherapy. Acta Biomater 9(7):7480–7489CrossRefGoogle Scholar
  75. Wang Y, Han N, Zhao Q, Bai L, Li J, Jiang T, Wang S (2015) Redox-responsive mesoporous silica as carriers for controlled drug delivery: a comparative study based on silica and PEG gatekeepers. Eur J Pharm Sci 72:12–20CrossRefGoogle Scholar
  76. Wu SH, Mou CY, Lin HP (2013) Synthesis of mesoporous silica nanoparticles. Chem Soc Rev 42(9):3862–3875CrossRefGoogle Scholar
  77. Yang J, Lee J, Kang J, Lee K, Suh JS, Yoon HG, Huh YM, Haam S (2008) Hollow silica nanocontainers as drug delivery vehicles. Langmuir 24:3417–3421CrossRefGoogle Scholar
  78. Yazaki Y, Oyane A, Tsurushima H, Araki H, Sogo Y, Ito A, Yamazaki A (2014) Coprecipitation of DNA-lipid complexes with apatite and comparison with superficial adsorption for gene transfer applications. J Biomater Appl 28(6):937–945CrossRefGoogle Scholar
  79. Yu T, Hubbard D, Ray A, Ghandehari H (2012) In vivo biodistribution and pharmacokinetics of silica nanoparticles as a function of geometry, porosity and surface characteristics. J Control Release 163:46–54CrossRefGoogle Scholar
  80. Zea C, Alcántara J, Barranco-García R, Morcillo M, de la Fuente D (2018) Synthesis and characterization of hollow mesoporous silica nanoparticles for smart corrosion protection. Nano 8:478Google Scholar
  81. Zhang X, Zheng F, Ye L, Xiong P, Yan L, Yang W, Jiang B (2014) A one-pot sol–gel process to prepare a superhydrophobic and environment-resistant thin film from ORMOSIL nanoparticles. RSC Adv 4:9838–9841CrossRefGoogle Scholar
  82. Zhao D (1998) Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores. Science 279:548–552CrossRefGoogle Scholar
  83. Zhao K, Rong G, Hao Y, Yu L, Kang H, Wang X, Wang X, Jin Z, Ren Z, Li Z (2016) IgA response and protection following nasal vaccination of chickens with Newcastle disease virus DNA vaccine nanoencapsulated with Ag@SiO2 hollow nanoparticles. Sci Rep 6:25720CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Sergio Rosales-Mendoza
    • 1
  • Omar González-Ortega
    • 2
  1. 1.Facultad de Ciencias Químicas, Centro de Investigación en Ciencias de la Salud y BiomedicinaUniversidad Autónoma de San Luis PotosíSan Luis PotosíMexico
  2. 2.Facultad de Ciencias QuímicasUniversidad Autónoma de San Luis Potosí San Luis PotosíMexico

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