Intracellular signaling pathway in dendritic cells and antigen transport pathway in vivo mediated by an OVA@DDAB/PLGA nano-vaccine

Shulan Han,Lianyan Wang,Weibo Cai,Jonathan W Engle,Logan Sutherlin,Xiaojie Xu,Dawei Jiang,Wenyan Ma,Jing Zhang,Zhao Chen,Yu Lu,Lei Kang,Nan Huo,Yanping Wang

doi:10.1186/s12951-021-01116-8

Abstract

BackgroundPoly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles have potential applications as a vaccine adjuvant and delivery system due to its unique advantages as biodegradability and biocompatibility.ExperimentalWe fabricated cationic solid lipid nanoparticles using PLGA and dimethyl-dioctadecyl-ammonium bromide (DDAB), followed by loading of model antigen OVA (antigen ovalbumin, OVA257-264) to form an OVA@DDAB/PLGA nano-vaccine. And we investigated the intracellular signaling pathway in dendritic cells in vitro and antigen transport pathway and immune response in vivo mediated by an OVA@DDAB/PLGA nano-vaccine.ResultsIn vitro experiments revealed that the antigen uptake of BMDCs after nanovaccine incubation was two times higher than pure OVA or OVA@Al at 12 h. The BMDCs were well activated by p38 MAPK signaling pathway. Furthermore, the nano-vaccine induced antigen escape from lysosome into cytoplasm with 10 times increased cross-presentation activity than those of OVA or OVA@Al. Regarding the transport of antigen into draining lymph nodes (LNs), the nano-vaccine could rapidly transfer antigen to LNs by passive lymphatic drainage and active DC transport. The antigen+ cells in inguinal/popliteal LNs for the nano-vaccine were increased over two folds comparing to OVA@Al and OVA at 12 h. Moreover, the antigen of nano-vaccine stayed in LNs for over 7 days, germinal center formation over two folds higher than those of OVA@Al and OVA. After immunization, the nano-vaccine induced a much higher ratio of IgG2c/IgG1 than OVA@Al. It also effectively activated CD4+ T, CD8+ T and B cells for immune memory with a strong cellular response.ConclusionThese results indicated that DDAB/PLGA NP was a potent platform to improve vaccine immunogenicity by p38 signaling pathway in BMDCs, enhancing transport of antigens to LNs, and higher immunity response.Graphical

Highlights

Vaccination plays a crucial role in controlling the dissemination of virus and reducing morbidity and mortality [1]
Han et al Journal of Nanobiotechnology (2021) 19:394. These results indicated that dioctadecyl-ammonium bromide (DDAB)/PLGA NP was a potent platform to improve vaccine immunogenicity by p38 signaling pathway in bone marrow‐derived dendritic cells (BMDCs), enhancing transport of antigens to lymph nodes (LNs), and higher immunity response
The results suggested that the OVA. Compared to pure antigen (OVA)@DDAB/PLGA Nv could promote more T and B cells activation than OVA and OVA-adsorbed Al (OVA@Al) (Fig. 7b–d and Additional file 1: Fig. S10b–d; for C D4+ T cells comparing with OVA, p < 0.01; for CD4+ T cells comparing with OVA@Al, p < 0.05; for CD8+ T cells comparing with OVA, p < 0.001; for CD8+ T cells comparing with OVA@ Al, p < 0.01; for CD19+ B cells comparing with OVA, p < 0.0001; for CD19+ B cells comparing with OVA@Al, p < 0.01)

Summary

Introduction

Vaccination plays a crucial role in controlling the dissemination of virus and reducing morbidity and mortality [1]. The ability of these vaccines to elicit a long-lasting and potent immune response is limited because their drawbacks as comparatively lower molecular weights and weaker immunogenicity [5]. Its application is limited by disadvantages such as side effects and anergy to cellular immunity, which drives the development of new delivery system and adjuvants for these subunit vaccines [8, 9]. Poly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles have potential applications as a vaccine adjuvant and delivery system due to its unique advantages as biodegradability and biocompatibility. Experimental: We fabricated cationic solid lipid nanoparticles using PLGA and dimethyl-dioctadecyl-ammonium bromide (DDAB), followed by loading of model antigen OVA (antigen ovalbumin, OVA257-264) to form an OVA@DDAB/ PLGA nano-vaccine. We investigated the intracellular signaling pathway in dendritic cells in vitro and antigen transport pathway and immune response in vivo mediated by an OVA@DDAB/PLGA nano-vaccine

Methods

Results

Conclusion