State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo 184-8588, Japan; Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei-shi, Tokyo 184-8588, Japan.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
J Control Release. 2024 Oct;374:312-324. doi: 10.1016/j.jconrel.2024.08.025. Epub 2024 Aug 21.
Controlled-release systems enhance anti-tumor effects by leveraging local antigen persistence for antigen-presenting cells (APCs) recruitment and T cell engagement. However, constant antigen presentation alone tends to induce dysfunction in tumor-specific CD8 T cells, neglecting the synergistic effects of co-stimulatory signal. To address this, we developed a soft particle-stabilized emulsion (SPE) to deliver lipopeptides with controlled release profiles by adjusting their hydrophobic chain lengths: C-SPE (fast release), C-SPE (medium release), and C-SPE (slow release). Following administration, C-SPE release antigen rapidly, inducing early antigen presentation, whereas C-SPE's slow-release delays antigen presentation. Both scenarios missed the critical window for coordinating with the expression of CD86, leading to either T cell apoptosis or suboptimal activation. In contrast, C-SPE achieved a spatiotemporally synergetic effect of the MHC-I-peptide complex and co-stimulatory signal (CD86), leading to effective dendritic cell (DC) activation, enhanced T cell activation, and tumor regression in EG7-OVA bearing mice. Additionally, co-delivery of cytosine-phosphate-guanine (CpG) with SPE provided a sustained expression of the CD86 window for DC activation, improving the immune response and producing robust anti-tumor effects with C-SPE comparable to C-SPE. These findings highlight that synchronizing the spatiotemporal dynamics of antigen presentation and APC activation may confer an optimal strategy for enhanced vaccinations.
控释系统通过利用局部抗原持续存在来招募抗原呈递细胞 (APC) 和 T 细胞参与，从而增强抗肿瘤作用。然而，仅持续的抗原呈递往往会导致肿瘤特异性 CD8 T 细胞功能障碍，忽略了共刺激信号的协同效应。为了解决这个问题，我们开发了一种软粒子稳定乳液 (SPE)，通过调整其疏水链长度来控制递送入体内的脂肽的释放：C-SPE（快速释放）、C-SPE（中速释放）和 C-SPE（慢速释放）。给药后，C-SPE 快速释放抗原，诱导早期抗原呈递，而 C-SPE 的缓慢释放则延迟抗原呈递。这两种情况都错过了与 CD86 表达相协调的关键窗口，导致 T 细胞凋亡或激活不足。相比之下，C-SPE 实现了 MHC-I-肽复合物和共刺激信号（CD86）的时空协同效应，有效激活树突状细胞 (DC)，增强 T 细胞激活，并在 EG7-OVA 荷瘤小鼠中引起肿瘤消退。此外，与 SPE 共递送胞嘧啶磷酸鸟嘌呤 (CpG) 可提供 DC 激活的共刺激信号 CD86 的持续表达，改善免疫反应，并产生与 C-SPE 相当的强大抗肿瘤作用。这些发现强调了同步抗原呈递和 APC 激活的时空动力学可能为增强疫苗接种提供一种优化策略。
