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

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.