肿瘤细胞治疗研究
英文原题：Selenium nanoparticles with bioorthogonal targeting to boost CAR-cell therapy for colorectal cancer.
嵌合抗原受体自然杀伤 (CAR-NK) 细胞疗法治疗实体瘤面临重大障碍，尤其是细胞浸润差和高度免疫抑制的肿瘤微环境 (TME)。
嵌合抗原受体自然杀伤（CAR-NK）细胞治疗实体瘤面临显著障碍，尤其是细胞浸润不足及高度免疫抑制性肿瘤微环境（TME）。为克服这些挑战，我们开发了含硒聚合物纳米颗粒（ManNAl-SeNPs），并负载二苯并环辛炔（DBCO）修饰的甘露糖。代谢糖工程（MGE）可在 CAR-NK 细胞的叠氮基（N₃）上高效标记外源 DBCO，由此建立生物正交点击化学靶向策略，显著提高叠氮化 CAR-NK（N₃-CAR-NK）细胞的抗肿瘤活性，包括识别特异性、迁移效率和细胞毒性。ManNAl-SeNPs 对酸性 TME 高度敏感，其二硒键响应后释放亚硒酸，发挥免疫检查点抑制作用，同时增强 CAR-NK 细胞毒性。体内联合使用 ManNAl-SeNPs 和 N₃-CAR-NK 细胞显著提高靶向能力及组织侵入性。本研究提出了一种 TME 响应型纳米平台及人工生物正交联合策略，可有效提高 CAR-NK 细胞迁移和蓄积，从而增强抗肿瘤治疗效果。
The treatment of solid tumors with chimeric antigen receptor natural killer (CAR-NK) cell therapy confronts significant barriers, notably poor cellular infiltration and a highly immunosuppressive tumor microenvironment (TME). To overcome these challenges, we developed selenium-containing polymer nanoparticles (ManNAl-SeNPs) loaded with dibenzocyclooctyne (DBCO)-modified mannose. Metabolic glycoengineering metabolic glycoengineering (MGE) enabled efficient labeling of exogenous DBCO on azide (N 3 ) groups on CAR-NK cells, establishing a bioorthogonal click chemistry targeting strategy, significantly improving the anti-tumor activity of azide-CAR-NK (N 3 -CAR-NK) cells, including recognition specificity, migration efficiency, and cytotoxic activity. Herein, ManNAl-SeNPs with ultra-sensitive responsiveness of diselenide bonds, in the acidic TME, diselenide bond releases seleninic acid, acting as an immune checkpoint inhibitor while augmenting CAR-NK cells cytotoxicity. In vivo, the combination of ManNAl-SeNPs with N 3 -CAR-NK cells significantly increased targeting capacity and invasiveness. This study presents a TME-responsive nanoplatform with artificial bio-orthogonal combination strategy that effectively enhance the migratory ability and accumulation of CAR-NK cells for potent antitumor therapy.
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