Lipid-polymer hybrid nanoparticles utilize B cells and dendritic cells to elicit distinct antigen-specific CD4⁺and CD8⁺T cell responses

Abstract

Antigen presenting cells (APCs) have been extensively studied for treating cancers and autoimmune diseases. Dendritic cells (DCs) are potent APCs that uptake and present antigens (Ags) to activate immunity or tolerance. Despite their active use in cellular immunotherapies, DCs face several challenges that hinder clinical translation, such as inability to control Ag dosing for tuning immune responses and low abundance in peripheral blood. B cells are a potential alternative to DCs, but their poor non-specific Ag uptake capabilities compromise controllable priming of T cells. We developed phospholipid-conjugated Ags (L-Ags) and lipid-polymer hybrid nanoparticles (L/P-Ag NPs) as Ag delivery platforms to expand the range of accessible APCs for use in priming CD4+ and CD8+ T cells. These delivery platforms were evaluated using DCs, CD40-activated B cells, and resting B cells as a diverse set of APCs to understand the impact of various Ag delivery mechanisms for generation of Ag-specific T cell responses. L-Ag delivery (termed depoting) of MHC class I and II-restricted Ags successfully loaded all APC types in a tunable manner and primed both Ag-specific CD8+ and CD4+ T cells, respectively. Incorporating L-Ags and polymer-conjugated Ags (P-Ag) into NPs can direct Ags to different uptake pathways to engineer the dynamics of presentation and shape T cell responses. DCs were capable of processing and presenting Ag delivered from both L- and P-Ag NPs yet B cells could only utilize Ag delivered from L-Ag NPs. Multivariate analysis of cytokines secreted from APC:T cell co-cultures indicated that L-Ag NPs primed different T cell responses than P-Ag NPs. Altogether, we show that L-Ags and P-Ags can be rationally paired within a single NP to leverage distinct delivery mechanisms to access multiple Ag processing pathways in two APC types, offering a modular delivery platform for engineering immunotherapies.