Different-Sized Gold Nanoparticle Activator/Antigen Increases Dendritic Cells Accumulation in Liver-Draining Lymph Nodes and CD8+ T Cell Responses

Abstract

The lack of efficient antigen and activator delivery systems, as well as the restricted migration of dendritic cells (DCs) to secondary lymph organs, dramatically limits DC-based adoptive immunotherapy. We selected two spherical gold nanoparticle (AuNP)-based vehicles of optimal size for activator and antigen delivery. Their combination (termed the NanoAu-Cocktail) was associated with the dual targeting of CpG oligonucleotides (CpG-ODNs) and an OVA peptide (OVAp) to DC subcellular compartments, inducing enhanced antigen cross-presentation, upregulated expression of costimulatory molecules and elevated secretion of T helper1 cytokines. We demonstrated that the intravenously transfused NanoAu-Cocktail pulsed DCs showed dramatically improved in vivo homing ability to lymphoid tissues and were settled in T cell area. Especially, by tissue-distribution analysis, we found that more than 60% of lymphoid tissues-homing DCs accumulated in liver-draining lymph nodes (LLNs). The improved homing ability of NanoAu-Cocktail pulsed DCs was associated with the high expression of chemokine receptor 7 (CCR7) and rearrangement of the cytoskeletons. In addition, by antigen-specific tetramers detection, NanoAu-Cocktail pulsed DCs were proved able to elicit strong antigen-specific CD8+ T cell responses, which provided enhanced protection from viral invasions. This study highlights the importance of codelivering antigen/adjuvant using different sized gold nanoparticles to improve DC homing and therapy.

Materials for Immunotherapy

“…In 2015, Jewell and co‐workers fabricated multilayer‐coated gold nanoparticles by the self‐assembly of polyelectrolytes comprising antigenic peptides and polyanionic TLR agonists, which were shown to significantly potentiate antigen‐specific T cell responses . A cocktail of gold nanoparticles with optimal sizes was developed by Zhan and co‐workers in 2016 to promote dendritic cell migration to liver‐draining lymph nodes and subsequently stimulate T cell responses . It was shown that the combination of 60 nm CpG‐conjugated gold nanoparticles and 80 nm OVA‐conjugated gold nanoparticles triggered dendritic cells to more effectively induce CD4 + and CD8 + T cell responses compared to their nanoparticle counterparts of different sizes.…”

Immunological Properties of Gold Nanoparticles

“…Modern trends in the use of GNPs for vaccination is the application of multivalent glycopolymers 202 and peptides; 57 combined use of GNPs and other immunostimulants, in particular CpG (including as conjugated with GNPs), 36,38,[221][222][223][224][225][226] polyvalent nucleic acid, 39,227 and plant adjuvants, e.g., extracts However, those data do not answer the question about the further mechanisms of antigen presentation to T helpers. According to the current view, 94 the presentation of an antigen to T cells is preceded by its processing, i.e., cleavage into peptide fragments followed by the formation of bonds with molecules of the major histocompatibility complex, which transport the antigen fragment to the surface of the antigen-presenting cell.…”

Engineering nanoparticles to overcome barriers to immunotherapy

“…In this situation, the optimal nanoparticle size maximizes dendritic cell uptake without inducing toxicity. Delivery of immune adjuvants (e.g., CpG) on the nanoparticles can enhance antigen copresentation and upregulate costimulatory molecule expression at the lymph nodes . To further enhance lymph node homing, nanoparticles can be coated with lipid membranes with incorporated ganglioside GM3.…”

“…Delivery of immune adjuvants (e.g., CpG) on the nanoparticles can enhance antigen copresentation and upregulate costimulatory molecule expression at the lymph nodes. 73 To further enhance lymph node homing, nanoparticles can be coated with lipid membranes with incorporated ganglioside GM3. This facilitates interaction with Siglec1 on myeloid dendritic cells and macrophages, which is responsible for B-cell, CD81 T-cell, and iNKT priming and activation.…”