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.

中文翻译：

---

脂质-聚合物混合纳米粒子利用 B 细胞和树突状细胞引发不同的抗原特异性 CD4+ 和 CD8+ T 细胞反应

抗原呈递细胞 (APC) 已被广泛研究用于治疗癌症和自身免疫性疾病。树突状细胞 (DC) 是有效的 APC，它们吸收和呈递抗原 (Ags) 以激活免疫或耐受性。尽管 DCs 在细胞免疫疗法中得到了积极的应用，但 DCs 面临着一些阻碍临床转化的挑战，例如无法控制 Ag 剂量以调节免疫反应和外周血中的低丰度。B 细胞是 DC 的潜在替代品，但它们较差的非特异性 Ag 摄取能力损害了 T 细胞的可控启动。我们开发了磷脂共轭银 (L-Ags) 和脂质-聚合物混合纳米粒子 (L/P-Ag NPs) 作为 Ag 递送平台，以扩大可用于引发 CD4 ⁺和 CD8 ^{+的 APC 的范围}T细胞。这些递送平台使用 DC、CD40 激活的 B 细胞和静息 B 细胞作为一组不同的 APC 进行了评估，以了解各种 Ag 递送机制对产生 Ag 特异性 T 细胞反应的影响。MHC I 类和 II 类限制性 Ags 的 L-Ag 递送（称为储存）以可调方式成功加载所有 APC 类型，并引发 Ag 特异性 CD8 ⁺和 CD4 ⁺T 细胞，分别。将 L-Ags 和聚合物共轭 Ags (P-Ag) 结合到 NPs 中可以将 Ags 引导到不同的摄取途径，以设计呈递动力学并塑造 T 细胞反应。DCs 能够处理和呈现从 L-和 P-Ag NPs 传递的 Ag，但 B 细胞只能利用从 L-Ag NPs 传递的 Ag。从 APC:T 细胞共培养物分泌的细胞因子的多变量分析表明，L-Ag NPs 引发了与 P-Ag NPs 不同的 T 细胞反应。总之，我们表明 L-Ags 和 P-Ags 可以在单个 NP 内合理配对，以利用不同的递送机制来访问两种 APC 类型中的多个 Ag 加工途径，为工程免疫疗法提供模块化递送平台。