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<p>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<sub>3</sub>) groups on CAR-NK cells, establishing a bioorthogonal click chemistry targeting strategy, significantly improving the anti-tumor activity of azide-CAR-NK (N<sub>3</sub>-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<sub>3</sub>-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.</p> Graphical abstract <p></p>

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Selenium nanoparticles with bioorthogonal targeting to boost CAR-cell therapy for colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Jinfan Zhou,
  • Gaohua Li,
  • Yunze Xu,
  • Wenhui Ma,
  • Xuehua Zhang,
  • Haitao Yuan,
  • Zilin Tan,
  • Zhenghao Li,
  • Hongwei Yu,
  • Zhenzhao Xu,
  • Zhiqiang Yu,
  • Jiafei Xi,
  • Chaoping Fu,
  • Yanan Wang

摘要

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 (N3) groups on CAR-NK cells, establishing a bioorthogonal click chemistry targeting strategy, significantly improving the anti-tumor activity of azide-CAR-NK (N3-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 N3-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.

Graphical abstract