氨基酸“标签化”纳米组装平台及其代谢免疫治疗

Amino Acid Delivery Platform by Tagging Nanoassembly for Immunometabolic Therapy

摘要: T细胞被认为是抗肿瘤的最主要细胞。近来，肿瘤主动诱导的氨基酸匮乏被发现是造成T细胞功能失调的重要因素，并由此催生了氨基酸代谢免疫疗法。然而，氨基酸递送存在重大瓶颈问题(负载量要求高，高亲水难负载，营养受体掠夺)。针对于此，本文作者提出发展一种适合不同氨基酸的标签化纳米组装平台并验证其代谢免疫治疗效果。具体策略是利用动态可逆的席夫碱键对氨基酸进行特定修饰(标签化)，进而利用铁离子诱导氨基酸标签化纳米组装。研究结果显示：标签化纳米组装实现了氨基酸高效负载目标(如精氨酸、甲硫氨酸负载率可达40%)，诱导了氨基酸颗粒具备光热及光声转换性能。体内结果表明：在低温光热(43℃)辅助下，氨基酸纳米粒可有效诱导CD8⁺ T淋巴细胞浸润至肿瘤组织(2.5倍高于PBS组)，肿瘤抑制率高达85%。本项目的实施不仅为氨基酸递送瓶颈提供解决思路，更为氨基酸代谢免疫治疗提供潜力技术。

Abstract: T cells are considered to be the main anti-tumor immune cells. It has been established that the scarcity of amino acids, mediated by tumor microenvironment, is the major reason for T cell dysfunction. This drives the emergence of amino acid immunometabolic cancer therapy. However, amino acid delivery poses major bottlenecks (highly hydrophilic for hard loading, nutrient receptor plaguing). Based on this, the applicant proposes to develop a universal amino acid delivery platform to realize personalized immunometabolic therapy. First, the strategy is to use dynamically reversible chemical bonds to modify the specific amino acids with small molecules (as the tag). The nano-assembly of amino acids is then achieved by adding ions to coordinate with tags. In this fashion, a loading efficiency of 40% and assembly induced photothermal and photoacoustic characteristics can be achieved. A mild heat of 43˚C on tumor by light irradiation stimulated the immunogenic cell death and effectively generated CD8⁺ T cells. Notably, Amino acids nanoparticles assisted by mild heat promoted 2.5-fold of tumor-infiltrating CD8⁺ T cells, leading to an inhibition ratio of 85% versus the PBS group. The implementation of this project provides not only an approach to address the delivery challenge of amino acid, but also a potential technology for im-munometabolic therapy.