Liposome and polymer-based nanomaterials for vaccine applications

Document Type : Review Paper


Clinical Immunology Department, Faculty of Medical Technology, Western University, T. Sralongrua, A. Huay Kra Chao, Kanchanaburi, Thailand, 71170


Nanoparticles (NPs) are effective and safe adjuvants for antigen delivery in modern vaccinology. Biodegradable nanomaterials with suitable properties are frequently applied for conjugation or loading with antigens; they protect the antigens from degradation in vivo. NPs are applied as effective delivery system to facilitate antigen uptake by antigen presenting cells (APCs) and especially dendritic cells (DCs) both in vitro and in vivo. Using nanoparticles to target DCs is an effective method to deliver antigens and potent immunomodulators. Uptake of NPs by DCs enhances the intracellular process of antigens and the antigen presentation pathway by MHC class I and II molecules to induce both CD4+ and CD8+ T-cell responses. Liposome and polymer-based NPs are now extensively applied as effective adjuvants or immunomodulators in several types of vaccines. In this review, the nanomaterials for vaccine application are focused intensively in poly(lactic-co-glycolic) acid (PLGA), dendrimers, liposomes, nanogels and micelles which are the targeted antigen delivery system, and present high potential as a promising future strategy for DNA-based, bacterial and viral vaccines. Further advances in nanotechnology and molecular immunology techniques will enhance the success of targeting and lead to the next generation of nano-delivery systems.


1.Oyewumi MO, Kumar A, Cui Z. Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses. Expert Rev Vaccines. 9(9): 1095-1097.
2.Reddy ST, Rehor A, Schmoekel HG, Hubbell JA, Swartz MA. In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J Control Release. 2006; 112(1): 26-34.
3.Bartlett DT, McAulay IR, Schrewe UJ, Schnuer K, Menzel HG, Bottollier-Depois JF. Dosimetry for occupational exposure to cosmic radiation. Radiat Prot Dosimetry. 1997; 70(1-4): 395-404.
4.Rice-Ficht AC, Arenas-Gamboa AM, Kahl-McDonagh MM, Ficht TA. Polymeric particles in vaccine delivery. Curr Opin Microbiol. 2010; 13(1): 106-1012.
5.Katare YK, Panda AK. Immunogenicity and lower dose requirement of polymer entrapped tetanus toxoid co-administered with alum. Vaccine. 2006; 24(17): 3599-3608.
6.Elamanchili P, Lutsiak CM, Hamdy S, Diwan M, Samuel J. “Pathogen-mimicking” nanoparticles for vaccine delivery to dendritic cells. J Immunother. 2007; 30(4): 378-395.
7.Kovacsovics-Bankowski M, Clark K, Benacerraf B, Rock KL. Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages. Proc Natl Acad Sci USA. 1993; 90(11): 4942-4946.
8.Abelev B, Adam J, Adamova D, Aggarwal MM, Aglieri Rinella G, Agnello M. Exclusive J/psi photoproduction off protons in ultraperipheral p-Pb collisions at radical(s(NN))=5.02 TeV. Phys Rev Lett. 2014; 113(23): 232504.
9.Panyam J, Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv Drug Deliv Rev. 2003; 55(3): 329-347.
10.Sarti F, Perera G, Hintzen F, Kotti K, Karageorgiou V, Kammona O. In vivo evidence of oral vaccination with PLGA nanoparticles containing the immunostimulant monophosphoryl lipid A. Biomaterials. 2011; 32(16): 4052-4057.
11.Reddy ST, Swartz MA, Hubbell JA. Targeting dendritic cells with biomaterials: developing the next generation of vaccines. Trends Immunol. 2006; 27(12): 573-579.
12.Newman KD, Sosnowski DL, Kwon GS, Samuel J. Delivery of MUC1 mucin peptide by Poly(d,l-lactic-co-glycolic acid) microspheres induces type 1 T helper immune responses. J Pharm Sci. 1998; 87(11): 1421-1427.
13.Nayak B, Ray AR, Panda AK, Ray P. Improved immunogenicity of biodegradable polymer particles entrapped rotavirus vaccine. J Biomater Appl. 2011; 25(5): 469-496.
14.Alonso MJ, Gupta RK, Min C, Siber GR, Langer R. Biodegradable microspheres as controlled-release tetanus toxoid delivery systems. Vaccine. 1994; 12(4): 299-306.
15.Audran R, Men Y, Johansen P, Gander B, Corradin G. Enhanced immunogenicity of microencapsulated tetanus toxoid with stabilizing agents. Pharm Res. 1998; 15(7): 1111-1116.
16.Katare YK, Panda AK, Lalwani K, Haque IU, Ali MM. Potentiation of immune response from polymer-entrapped antigen: toward development of single dose tetanus toxoid vaccine. Drug Deliv. 2003; 10(4): 231-238.
17.Raghuvanshi RJ, Mistra A, Talwar GP, Levy RJ, Labhasetwar V. Enhanced immune response with a combination of alum and biodegradable nanoparticles containing tetanus toxoid. J Microencapsul. 2001; 18(6): 723-732.
18.Raghuvanshi RS, Singh O, Panda AK. Formulation and characterization of immunoreactive tetanus toxoid biodegradable polymer particles. Drug Deliv. 2001; 8(2): 99-106.
19.Raghuvanshi RS, Katare YK, Lalwani K, Ali MM, Singh O, Panda AK. Improved immune response from biodegradable polymer particles entrapping tetanus toxoid by use of different immunization protocol and adjuvants. Int J Pharm. 2002; 245(1-2): 109-121.
20.Raghuvanshi RS, Singh O, Panda AK. Correlation between in vitro release and in vivo immune response from biodegradable polymer particles entrapping tetanus toxoid. Drug Deliv. 2002; 9(2): 113-120.
21.Tian J, Sun X, Chen X, Yu J, Qu L, Wang L. The formulation and immunisation of oral poly(DL-lactide-co-glycolide) microcapsules containing a plasmid vaccine against lymphocystis disease virus in Japanese flounder (Paralichthys olivaceus). Int Immunopharmacol. 2008; 8(6): 900-908.
22.Trombone AP, Silva CL, Almeida LP, Rosada RS, Lima KM, Oliver C. Tissue distribution of DNA-Hsp65/TDM-loaded PLGA microspheres and uptake by phagocytic cells. Genet Vaccines Ther. 2007; 5: 9.
23.Demento SL, Eisenbarth SC, Foellmer HG, Platt C, Caplan MJ, Mark Saltzman W, Mellman I, Ledizet M, Fikrig E, Flavell RA, Fahmy TM. Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy. Vaccine. 2009; 27(23): 3013-3021.
24.Hamdy S, Molavi O, Ma Z, Haddadi A, Alshamsan A, Gobti Z. Co-delivery of cancer-associated antigen and Toll-like receptor 4 ligand in PLGA nanoparticles induces potent CD8+ T cell-mediated anti-tumor immunity. Vaccine. 2008; 26(39): 5046-5057.
25.Goforth R, Salem AK, Zhu X, Miles S, Zhang XQ, Lee JH. Immune stimulatory antigen loaded particles combined with depletion of regulatory T-cells induce potent tumor specific immunity in a mouse model of melanoma. Cancer Immunol Immunother. 2009; 58(4): 517-530.
26.Heit A, Schmitz F, Haas T, Busch DH, Wagner H. Antigen co-encapsulated with adjuvants efficiently drive protective T cell immunity. Eur J Immunol. 2007; 37(8): 2063-2074.
27.Lee YR, Lee YH, Im SA, Yang IH, Ahn GW, Kim K, Lee CK. Biodegradable nanoparticles containing TLR3 or TLR9 agonists together with antigen enhance MHC-restricted presentation of the antigen. Arch Pharm Res. 2010; 33(11): 1859-1866.
28.San Roman B, Irache JM, Gomez S, Tsapis N, Gamazo C, Espuelas MS. Co-encapsulation of an antigen and CpG oligonucleotides into PLGA microparticles by TROMS technology. Eur J Pharm Biopharm. 2008; 70(1): 98-108.
29.Shen H, Ackerman AL, Cody V, Giodini A, Hinson ER, Cresswell P. Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles. Immunology. 2006; 117(1): 78-88.
30.Song C, Noh YW, Lim YT. Polymer nanoparticles for cross-presentation of exogenous antigens and enhanced cytotoxic T-lymphocyte immune response. Int J Nanomedicine. 2016; 11: 3753-3764.
31.Aline F, Brand D, Pierre J, Roingeard P, Severine M, Verrier B. Dendritic cells loaded with HIV-1 p24 proteins adsorbed on surfactant-free anionic PLA nanoparticles induce enhanced cellular immune responses against HIV-1 after vaccination. Vaccine. 2009; 27(38): 5284-5291.
32.Stanley AC, Buxton D, Innes EA, Huntley JF. Intranasal immunisation with Toxoplasma gondii tachyzoite antigen encapsulated into PLG microspheres induces humoral and cell-mediated immunity in sheep. Vaccine. 2004; 22(29-30): 3929-3941.
33.O’Brien CN, Guidry AJ, Fattom A, Shepherd S, Douglass LW, Westhoff DC. Production of antibodies to Staphylococcus aureus serotypes 5, 8, and 336 using poly(DL-lactide-co-glycolide) microspheres. J Dairy Sci. 2000; 83(8): 1758-1766.
34.Suckow MA, Bowersock TL, Park H, Park K. Oral immunization of rabbits against Pasteurella multocida with an alginate microsphere delivery system. J Biomater Sci Polym Ed. 1996; 8(2): 131-139.
35.Aucouturier J, Dupuis L, Ganne V. Adjuvants designed for veterinary and human vaccines. Vaccine. 2001; 19(17-19): 2666-2672.
36.He XW, Wang F, Jiang L, Li J, Liu SK, Xiao ZY. Induction of mucosal and systemic immune response by single-dose oral immunization with biodegradable microparticles containing DNA encoding HBsAg. J Gen Virol. 2005; 86(Pt 3): 601-610.
37.Najlah M, D’Emanuele A. Crossing cellular barriers using dendrimer nanotechnologies. Curr Opin Pharmacol. 2006; 6(5): 522-527.
38.Barouch DH. Rational design of gene-based vaccines. J Pathol. 2006; 208(2): 283-289.
39.Pietersz GA, Tang CK, Apostolopoulos V. Structure and design of polycationic carriers for gene delivery. Mini Rev Med Chem. 2006; 6(12): 1285-1298.
40.Tekade RK, Kumar PV, Jain NK. Dendrimers in oncology: an expanding horizon. Chem Rev. 2009; 109(1): 49-87.
41.Agadjanyan MG, Ghochikyan A, Petrushina I, Vasilevko V, Movsesyan N, Mkrtichyan M. Prototype Alzheimer’s disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol. 2005; 174(3): 1580-1586.
42.Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues. J pharm bioallied sci. 2014; 6(3): 139-150.
43.Dutta T, Garg M, Jain NK. Poly(propyleneimine) dendrimer and dendrosome mediated genetic immunization against hepatitis B. Vaccine. 2008; 26(27-28): 3389-3394.
44.Rupp R, Rosenthal SL, Stanberry LR. VivaGel (SPL7013 Gel): a candidate dendrimer--microbicide for the prevention of HIV and HSV infection. Int J Nanomedicine. 2007; 2(4): 561-566.
45.Chaves F, Calvo JC, Carvajal C, Rivera Z, Ramirez L, Pinto M. Synthesis, isolation and characterization of Plasmodium falciparum antigenic tetrabranched peptide dendrimers obtained by thiazolidine linkages. J Pept Res. 2001; 58(4): 307-316.
46.Sauerwein RW, Roestenberg M, Moorthy VS. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol. 2011; 11(1): 57-64.
47.Tam JP, Clavijo P, Lu YA, Nussenzweig V, Nussenzweig R, Zavala F. Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria. J Exp Med. 1990; 171(1): 299-306.
48.Daftarian P, Kaifer AE, Li W, Blomberg BB, Frasca D, Roth F. Peptide-conjugated PAMAM dendrimer as a universal DNA vaccine platform to target antigen-presenting cells. Cancer Res. 2011; 71(24): 7452-7462.
49.Allison AG, Gregoriadis G. Liposomes as immunological adjuvants. Nature. 1974; 252(5480): 252.
50.Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine. 2006; 1(3): 297-315.
51.Baca-Estrada ME, Foldvari M, Snider M, van Drunen Littel-van den Hurk S, Babiuk LA. Effect of IL-4 and IL-12 liposomal formulations on the induction of immune response to bovine herpesvirus type-1 glycoprotein D. Vaccine. 1997; 15(16): 1753-1760.
52.Demana PH, Fehske C, White K, Rades T, Hook S. Effect of incorporation of the adjuvant Quil A on structure and immune stimulatory capacity of liposomes. Immunol Cell Biol. 2004; 82(5): 547-554.
53.Kersten GF, Crommelin DJ. Liposomes and ISCOMs. Vaccine. 2003; 21(9-10): 915-920.
54.Giddam AK, Zaman M, Skwarczynski M, Toth I. Liposome-based delivery system for vaccine candidates: constructing an effective formulation. Nanomedicine (Lond). 2012; 7(12): 1877-1893.
55.Brockstedt DG, Giedlin MA, Leong ML, Bahjat KS, Gao Y, Luckett W. Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc Natl Acad Sci U S A. 2004; 101(38): 13832-13837.
56.Gregoriadis G. Drug entrapment in liposomes. FEBS Lett. 1973; 36(3): 292-296.
57.Guo X, Szoka FC, Jr. Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG--diortho ester--lipid conjugate. Bioconjug Chem. 2001; 12(2): 291-300.
58.Adu-Bobie J, Capecchi B, Serruto D, Rappuoli R, Pizza M. Two years into reverse vaccinology. Vaccine. 2003; 21(7-8): 605-610.
59.Tseng LP, Chiou CJ, Deng MC, Lin MH, Pan RN, Huang YY. Evaluation of encapsulated Newcastle disease virus liposomes using various phospholipids administered to improve chicken humoral immunity. J Biomed Mater Res B Appl Biomater. 2009; 91(2): 621-625.
60.Ghaffar KA, Marasini N, Giddam AK, Batzloff MR, Good MF, Skwarczynski M. Liposome-based intranasal delivery of lipopeptide vaccine candidates against group A streptococcus. Acta Biomater. 2016; 41: 161-168.
61.Chiavolini D, Weir S, Murphy JR, Wetzler LM. Neisseria meningitidis PorB, a Toll-like receptor 2 ligand, improves the capacity of Francisella tularensis lipopolysaccharide to protect mice against experimental tularemia. Clin Vaccine Immunol. 2008; 15(9): 1322-1329.
62.Link C, Gavioli R, Ebensen T, Canella A, Reinhard E, Guzman CA. The Toll-like receptor ligand MALP-2 stimulates dendritic cell maturation and modulates proteasome composition and activity. Eur J Immunol. 2004; 34(3): 899-907.
63.Nordly P, Madsen HB, Nielsen HM, Foged C. Status and future prospects of lipid-based particulate delivery systems as vaccine adjuvants and their combination with immunostimulators. Expert Opin Drug Deliv. 2009; 6(7): 657-672.
64.Espuelas S, Roth A, Thumann C, Frisch B, Schuber F. Effect of synthetic lipopeptides formulated in liposomes on the maturation of human dendritic cells. Mol Immunol. 2005; 42(6): 721-729.
65.Altin JG, Parish CR. Liposomal vaccines--targeting the delivery of antigen. Methods. 2006; 40(1): 39-52.
66.Liang MT, Davies NM, Toth I. Encapsulation of lipopeptides within liposomes: effect of number of lipid chains, chain length and method of liposome preparation. Int J Pharm. 2005; 301(1-2): 247-254.
67.Carstens MG, Camps MG, Henriksen-Lacey M, Franken K, Ottenhoff TH, Perrie Y. Effect of vesicle size on tissue localization and immunogenicity of liposomal DNA vaccines. Vaccine. 2011; 29(29-30): 4761-4770.
68.Henriksen-Lacey M, Devitt A, Perrie Y. The vesicle size of DDA:TDB liposomal adjuvants plays a role in the cell-mediated immune response but has no significant effect on antibody production. J Control Release. 2011; 154(2): 131-137.
69.Skwarczynski M, Toth I. Peptide-based subunit nanovaccines. Curr Drug Deliv. 2011; 8(3): 282-289.
70.Gao J, Yu Y, Zhang Y, Song J, Chen H, Li W. EGFR-specific PEGylated immunoliposomes for active siRNA delivery in hepatocellular carcinoma. Biomaterials. 2012; 33(1): 270-282.
71.Zhuang Y, Ma Y, Wang C, Hai L, Yan C, Zhang Y. PEGylated cationic liposomes robustly augment vaccine-induced immune responses: Role of lymphatic trafficking and biodistribution. J Control Release. 2012; 159(1): 135-142.
72.Kaur R, Bramwell VW, Kirby DJ, Perrie Y. Pegylation of DDA:TDB liposomal adjuvants reduces the vaccine depot effect and alters the Th1/Th2 immune responses. J Control Release. 2012; 158(1): 72-77.
73.Chonn A, Semple SC, Cullis PR. Association of blood proteins with large unilamellar liposomes in vivo. Relation to circulation lifetimes. J Biol Chem. 1992; 267(26): 18759-18765.
74.Oja CD, Semple SC, Chonn A, Cullis PR. Influence of dose on liposome clearance: critical role of blood proteins. Biochim Biophys Acta. 1996; 1281(1): 31-37.
75.Korsholm KS, Andersen PL, Christensen D. Cationic liposomal vaccine adjuvants in animal challenge models: overview and current clinical status. Expert Rev Vaccines. 2012; 11(5): 561-577.
76.Ferreira SA, Gama FM, Vilanova M. Polymeric nanogels as vaccine delivery systems. Nanomedicine. 2013; 9(2): 159-173.
77.Coviello T, Matricardi P, Marianecci C, Alhaique F. Polysaccharide hydrogels for modified release formulations. J Control Release. 2007; 119(1): 5-24.
78.Cabral GA, Ferreira GA, Jamerson MJ. Endocannabinoids and the Immune System in Health and Disease. Handb Exp Pharmacol. 2015; 231: 185-211.
79.Wu QJ, Zhu XC, Xiao X, Wang P, Xiong da K, Gong CY. A novel vaccine delivery system: biodegradable nanoparticles in thermosensitive hydrogel. Growth Factors. 2011; 29(6): 290-297.
80.Schuler G, Steinman RM. Dendritic cells as adjuvants for immune-mediated resistance to tumors. J Exp Med. 1997; 186(8): 1183-1187.
81.Nochi T, Yuki Y, Takahashi H, Sawada S, Mejima M, Kohda T. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines. Nat Mater. 2010; 9(7): 572-578.
82.Debache K, Kropf C, Schutz CA, Harwood LJ, Kauper P, Monney T, Rossi N, Laue C, McCullough KC, Hemphill A. Vaccination of mice with chitosan nanogel-associated recombinant NcPDI against challenge infection with Neospora caninum tachyzoites. Parasite Immunol. 2011; 33(2): 81-94.
83.Aderibigbe BA, Naki T. Design and Efficacy of Nanogels Formulations for Intranasal Administration. Molecules. 2018; 23(6); 1241.
84.Hirosue S, Kourtis IC, van der Vlies AJ, Hubbell JA, Swartz MA. Antigen delivery to dendritic cells by poly(propylene sulfide) nanoparticles with disulfide conjugated peptides: Cross-presentation and T cell activation. Vaccine. 2010; 28(50): 7897-7906.
85.Selvam R, Devaraj S. Oxalate binding to rat kidney mitochondria: induction by oxidized glutathione. Indian J Biochem Biophys. 1996; 33(1): 62-65.
86.Trimaille T, Verrier B. Micelle-Based Adjuvants for Subunit Vaccine Delivery. Vaccines. 2015; 3(4): 803-813.
87.[Treatment in every detected virus replication. New guideline for therapy of hepatitis B publicized]. MMW Fortschr Med. 2007; 149(29-30): 61.
88.Xiong XB, Falamarzian A, Garg SM, Lavasanifar A. Engineering of amphiphilic block copolymers for polymeric micellar drug and gene delivery. J Control Release. 2011; 155(2): 248-261.
89.Boudier A, Aubert-Pouessel A, Louis-Plence P, Gerardin C, Jorgensen C, Devoisselle JM. The control of dendritic cell maturation by pH-sensitive polyion complex micelles. Biomaterials. 2009; 30(2): 233-241.
90.Boudier A, Aubert-Pouessel A, Mebarek N, Chavanieu A, Quentin J, Martire D, Boukhaddaoui H, Gérardin C, Jorgensen C, Devoisselle JM, Louis-Plence P, Bégu S. Development of tripartite polyion micelles for efficient peptide delivery into dendritic cells without altering their plasticity. J Control Release. 2011; 154(2): 156-163.
91.Jain AK, Goyal AK, Gupta PN, Khatri K, Mishra N, Mehta A. Synthesis, characterization and evaluation of novel triblock copolymer based nanoparticles for vaccine delivery against hepatitis B. J Control Release. 2009; 136(2): 161-169.
92.Jain AK, Goyal AK, Mishra N, Vaidya B, Mangal S, Vyas SP. PEG-PLA-PEG block copolymeric nanoparticles for oral immunization against hepatitis B. Int J Pharm. 2010; 387(1-2): 253-262.
93.Luo L, Qin T, Huang Y, Zheng S, Bo R, Liu Z. Exploring the immunopotentiation of Chinese yam polysaccharide poly(lactic-co-glycolic acid) nanoparticles in an ovalbumin vaccine formulation in vivo. Drug Deliv. 2017; 24(1): 1099-1111.
94.Ellebedy AH, Ducatez MF, Duan S, Stigger-Rosser E, Rubrum AM, Govorkova EA,Webster RG, Webby RJ. Impact of prior seasonal influenza vaccination and infection on pandemic A (H1N1) influenza virus replication in ferrets. Vaccine. 2011; 29(17):3335-3339.
95.Noh YW, Hong JH, Shim SM, Park HS, Bae HH, Ryu EK. Polymer nanomicelles for efficient mucus delivery and antigen-specific high mucosal immunity. Angew Chem Int Ed Engl. 2013; 52(30): 7684-7689.
96.Luo Z, Li P, Deng J, Gao N, Zhang Y, Pan H. Cationic polypeptide micelle-based antigen delivery system: a simple and robust adjuvant to improve vaccine efficacy. J Control Release. 2013; 170(2): 259-267.
97.Leroux-Roels I, Koutsoukos M, Clement F, Steyaert S, Janssens M, Bourguignon P. Strong and persistent CD4+ T-cell response in healthy adults immunized with a candidate HIV-1 vaccine containing gp120, Nef and Tat antigens formulated in three Adjuvant Systems. Vaccine. 2010; 28(43): 7016-7024.
98.Gluck R, Metcalfe IC. New technology platforms in the development of vaccines for the future. Vaccine. 2002; 20 Suppl 5: B10-6.
99.Gluck R. Adjuvant activity of immunopotentiating reconstituted influenza virosomes (IRIVs). Vaccine. 1999; 17(13-14): 1782-1787.