自添加 L-精氨酸修饰的葡聚糖基纳米凝胶,用于向抗原递呈细胞持续递送局部抗原蛋白并增强细胞和体液免疫反应。

IF 5.7 3区 医学 Q1 MATERIALS SCIENCE, BIOMATERIALS
Jin Teng Chung, Mehrnoosh Rafiei and Ying Chau
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引用次数: 0

摘要

在开发癌症疫苗的过程中,抗原的传递会引起有效和特异的 T 细胞反应,从而消灭肿瘤细胞。然而,由于肿瘤抗原的免疫原性差、先天性免疫快速清除以及在 MHC-I 上的交叉呈递有限,无法激活 CD8+ T 细胞臂,疫苗的成功往往受到阻碍。为了解决这些问题,我们开发了葡聚糖基纳米凝胶,以促进抗原的摄取、储存和在 MHC-I 上的交叉呈递,同时引导抗原呈递细胞(APCs)的免疫原性成熟。为了促进纳米载体与细胞的相互作用,我们用 L-精氨酸(Arg)对 DX 进行了修饰,其免疫调节活性已得到充分证实。我们将 ArgDX 纳米凝胶的性能与用 L-组氨酸(His)和 L-谷氨酸(Glut)修饰的纳米凝胶进行了比较。此外,我们还在纳米凝胶形成过程中引入了对 pH 值敏感的腙交联,以实现抗原卵清蛋白(OVA)的共轭和控释。负载 OVA 的纳米凝胶平均尺寸为 325 nm。我们证明,当 pH 值从 7 变为 5 时,纳米凝胶可在 8 天内迅速释放货物,这表明抗原在酸性细胞区室中被内化后可控释放。我们的研究结果表明,ArgDX 纳米凝胶能促进体外直流细胞对抗原的摄取和储存,并促进直流细胞的免疫原性成熟和巨噬细胞的 M1 极化。OVA 信号与溶酶体共定位,直到处理和洗涤后的 96 小时,这表明纳米凝胶可促进内溶酶体的长期抗原储存和供应。此外,所有测试的纳米凝胶配方都能在皮肤注射部位保留抗原直至第 21 天。这种延迟清除可能是由于含有 OVA 的纳米凝胶形成了微米大小的聚集体,从而延长了与常驻 DC 的相互作用。在各种氨基酸修饰中,ArgDX 纳米凝胶对直流细胞淋巴结归巢信号 CCR7 的促进作用最高。与 DX 相比,纳米凝胶在体外 MHC-I 和 II 上的抗原呈递率也更高。在体内免疫研究中,治疗后第 21 天,ArgDX 纳米凝胶在诱导细胞免疫和体液免疫方面优于其他治疗组。这些结果表明,ArgDX 纳米凝胶是一种很有前景的用于疫苗递送的自佐剂纳米载体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Self-adjuvanted l-arginine-modified dextran-based nanogels for sustained local antigenic protein delivery to antigen-presenting cells and enhanced cellular and humoral immune responses†

Self-adjuvanted l-arginine-modified dextran-based nanogels for sustained local antigenic protein delivery to antigen-presenting cells and enhanced cellular and humoral immune responses†

Self-adjuvanted l-arginine-modified dextran-based nanogels for sustained local antigenic protein delivery to antigen-presenting cells and enhanced cellular and humoral immune responses†

In the development of cancer vaccines, antigens are delivered to elicit potent and specific T-cell responses to eradicate tumour cells. Nonetheless, successful vaccines are often hampered by the poor immunogenicity of tumour antigens, rapid clearance by the innate immunity, and limited cross-presentation on MHC-I to activate CD8+ T-cells arm. To address these issues, we developed dextran-based nanogels to promote antigen uptake, storage, and cross-presentation on MHC-I, while directing immunogenic maturation of the antigen-presenting cells (APCs). To promote the nanocarriers interaction with cells, we modified DX with L-arginine (Arg), whose immunomodulatory activities have been well documented. The ArgDX nanogel performance was compared with the nanogel modified with L-histidine (His) and L-glutamate (Glut). Moreover, we introduced pH-sensitive hydrazone crosslinking during the nanogel formation for the conjugation and controlled release of antigen ovalbumin (OVA). The OVA-laden nanogels have an average size of 325 nm. We demonstrated that the nanogels could rapidly release cargoes upon a pH change from 7 to 5 within 8 days, indicating the controlled release of antigens in the acidic cellular compartments upon internalization. Our results revealed that the ArgDX nanogel could promote greater antigen uptake and storage in DCs in vitro and promoted a stronger immunogenic maturation of DCs and M1 polarization of the macrophages. The OVA signals were co-localized with lysosomal compartments up till 96 hours post-treatment and washing, suggesting the nanogels could facilitate prolonged antigen storage and supply from endo-lysosomal compartments. Furthermore, all the tested nanogel formulations retained antigens at the skin injection sites until day 21. Such delayed clearance could be due to the formation of micron-sized aggregates of OVA-laden nanogels, extending the interactions with the resident DCs. Amongst the amino acid modifications, ArgDX nanogels promoted the highest level of lymph node homing signal CCR7 on DCs. The nanogels also showed higher antigen presentation on both MHC-I and II than DX in vitro. In the in vivo immune studies, ArgDX nanogels were more superior in inducing cellular and humoral immunity than the other treatment groups on day 21 post-treatment. These results suggested that ArgDX nanogel is a promising self-adjuvanted nanocarrier for vaccine delivery.

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来源期刊
Biomaterials Science
Biomaterials Science MATERIALS SCIENCE, BIOMATERIALS-
CiteScore
11.50
自引率
4.50%
发文量
556
期刊介绍: Biomaterials Science is an international high impact journal exploring the science of biomaterials and their translation towards clinical use. Its scope encompasses new concepts in biomaterials design, studies into the interaction of biomaterials with the body, and the use of materials to answer fundamental biological questions.
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