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) are widely studied for treating immunemediated diseases, and dendritic cells (DCs) are potent APCs that uptake and present antigens (Ags). However, DCs face several challenges that hinder their clinical translation due to their inability to control Ag dosing and low abundance in peripheral blood. B cells are a potential alternative to DCs, but their poor nonspecific Ag uptake capabilities compromise controllable priming of T cells. Here, we developed phospholipid-conjugated Ags (L-Ags) and lipid−polymer hybrid nanoparticles (L/P-Ag NPs) as delivery platforms to expand the range of accessible APCs for use in T cell priming. These delivery platforms were evaluated using DCs, CD40-activated B cells, and resting B cells to understand the impacts 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, which led to differential cytokine secretion profiles in coculture studies. 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 Ag-specific immunotherapies.

Advances in Nonviral mRNA Delivery Materials and Their Application as Vaccines for Melanoma Therapy

“…While lipids and polymers alone are capable of delivering mRNA, combining these materials into hybrid nanoparticles can further promote cellular uptake, facilitate endosomal escape of therapeutic cargo, and improve antigen-specific T cell responses. , Lipopolyplexes are a commonly used nonviral hybrid carrier for nucleic acid delivery. Since they are composed of a polymeric core and a lipid shell, they are designed to synergize the strengths of both lipids and polymers to generate nanoparticles with better stability, decreased cytotoxicity, and enhanced transfection efficiency .…”

Development of Protein–Polymer Conjugate Nanoparticles for Modulation of Dendritic Cell Phenotype and Antigen-Specific CD4 T Cell Responses

“…Our previous work developed peptide Ag-conjugated NPs (acNP-Ag) to overcome the noted limitations of NP-sAg and NP­(Ag). , The carboxyl end group of poly­(lactic-co-glycolic acid) (PLGA) was conjugated with the N-terminus of peptide Ags, which were then systematically combined at predefined ratios with unmodified PLGA to form acNP-Ags. The induction of Tregs in vitro required the delivery of acNP with a minimum Ag loading of 8 μg/mg to maximize T cell differentiation, which could not be overcome with increasing NP concentration.…”