title: pH-Responsive Poly(D,L-lactic-co-glycolic acid) Nanoparticles with Rapid Antigen Release Behavior Promote Immune Response.
abstract: In the quest to treat intracellular infectious diseases and virus infection, nanoparticles (NPs) have been considered to be efficient tools for inducing potent immune responses, specifically cellular immunity. Antigen processing and presenting by antigen presenting cells (APCs) could influence immune response, especially the priming of T-cell-mediated cellular immunity. Here, we fabricated pH-responsive poly(D,L-lactic-co-glycolic acid) (PLGA) NPs with rapid antigen intracellular release behavior in APCs. The NPs, which had thin shells and large inner space, contain ammonium bicarbonate (NH4HCO3), which could regulate release in endosomes and lysosomes, acting as an antigen release promoter in dendritic cells (DCs), and were coencapsulated with antigen (ovalbumin, OVA). Hydrogen ions (H(+)) in DC endosomes and lysosomes (pH ∼5.0 and 6.5) could react with NH4HCO3 to generate NH3 and CO2, which broke NPs and released antigens. After uptake by DCs, antigens encapsulated in pH-responsive PLGA NPs could escape from lysosomes into the cytoplasm and be cross-presented. Moreover, the NPs induced up-regulation of co-stimulatory molecules and stimulated cytokine production. Mouse immunization with pH-responsive PLGA NPs induced greater lymphocyte activation, more antigen-specific CD8(+) T cells, stronger cytotoxic capacity (IFN-γ and granzyme B), enhanced antigen-specific IgG antibodies, and higher serum IgG2a/IgG1, indicating cellular immunity. The NPs also improved generation of memory T cells to protect against reinfection. Thus, pH-responsive PLGA NPs, which induced strong cellular immune responses and offered antibody protection, could be potentially useful as effective vaccine delivery and adjuvant systems for the therapy of intracellular infectious diseases and virus infection.
authors.affiliation: ‡University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: ‡University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Chen
authors.affiliation: ‡University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
authors.forename: Jilei
authors.initials: J
authors.lastname: Jia
authors.affiliation: ‡University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Zhang
authors.forename: Tingyuan
authors.initials: T
authors.lastname: Yang
authors.forename: Lianyan
authors.initials: L
authors.lastname: Wang
authors.affiliation: §Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, 300072, People's Republic of China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ma
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry* / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration; D007111:Immunity, Cellular; D042541:Intracellular Space / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013997:Time Factors; D014612:Vaccines / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D004337:Drug Carriers; D014612:Vaccines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin
keywords: PLGA nanoparticles; antigen intracellular rapid release; dendritic cells; pH-responsive; vaccine delivery and adjuvant system