Kimura Ryouken, Yamano Tomoyoshi, Onishi Uryo, Lyu Xiabing, Nagamori Kanto, Van Le Toan, Nakada Mitsutoshi, Hanayama Rikinari
Department of Immunology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Department of Neurosurgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Drug Deliv. 2025 Dec;32(1):2509969. doi: 10.1080/10717544.2025.2509969. Epub 2025 Jun 12.
Extracellular vesicles (EVs), particularly small EVs (sEVs), are lipid bilayer vesicles secreted by various cell types and play a key role in intercellular communication. These vesicles are promising tools for cancer immunotherapy owing to their biocompatibility, low immunogenicity, and capacity for targeted drug delivery. In this study, we aimed to assess the potential of engineered antigen-presenting EVs (AP-EVs) to selectively expand and differentiate antigen-specific CD4 T cells. We engineered two types of AP-EVs: AP-EVs-Th1 expressing MHC class II, CD80, and interleukin (IL)-12 on their surface to promote Th1 differentiation, and AP-EVs-Th2 expressing MHC class II, CD80, and IL-4 to induce Th2 differentiation. experiments demonstrated that AP-EVs successfully induced the antigen-specific proliferation and differentiation of Th1 and Th2 cells, respectively. Notably, administration of AP-EVs-Th1 significantly enhanced the proliferation and differentiation of tumor antigen-specific Th1 cells, leading to robust anti-tumor effects in a murine melanoma model. These findings highlight the potential of AP-EVs-Th1 for cancer immunotherapy, particularly in augmenting CD4 T cell responses. Furthermore, the versatility and adaptability of EV-based therapies make them beneficial for the development of personalized immunotherapeutic strategies for various cancer types, offering the advantages of targeted immune modulation, ease of use, and reduced risk compared to cell-based therapies.
细胞外囊泡（EVs），尤其是小细胞外囊泡（sEVs），是由多种细胞类型分泌的脂质双层囊泡，在细胞间通讯中起关键作用。由于其生物相容性、低免疫原性和靶向药物递送能力，这些囊泡是癌症免疫治疗的有前景的工具。在本研究中，我们旨在评估工程化抗原呈递细胞外囊泡（AP-EVs）选择性扩增和分化抗原特异性CD4 T细胞的潜力。我们构建了两种类型的AP-EVs：表面表达MHC II类分子、CD80和白细胞介素（IL）-12以促进Th1分化的AP-EVs-Th1，以及表达MHC II类分子、CD80和IL-4以诱导Th2分化的AP-EVs-Th2。实验表明，AP-EVs分别成功诱导了Th1和Th2细胞的抗原特异性增殖和分化。值得注意的是，给予AP-EVs-Th1显著增强了肿瘤抗原特异性Th1细胞的增殖和分化，在小鼠黑色素瘤模型中产生了强大的抗肿瘤作用。这些发现突出了AP-EVs-Th1在癌症免疫治疗中的潜力，特别是在增强CD4 T细胞反应方面。此外，基于细胞外囊泡的疗法的多功能性和适应性使其有利于开发针对各种癌症类型的个性化免疫治疗策略，与基于细胞的疗法相比，具有靶向免疫调节、使用方便和风险降低的优点。
