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Genetically engineered T cell therapy is emerging as a potent strategy for treating hematological and solid malignancies. Although lentivirus is the most common vector for T cell gene modification, its transduction efficacy remains unsatisfied especially during the manufacturing process. Herein, glycometabolic bioorthogonal chemistry is utilized to establish a highly efficient viral transduction system for human primary T lymphocytes. Azide motifs are anchored on the T cell surface via the intrinsic glycometabolism of exogenous azide–glucose, serving as an artificial ligand for viral binding. The complementary functional moiety dibenzocyclooctyl (DBCO)‐conjugated PEI1.8K (PEI‐DBCO) is then coated on lentiviral surface, which strengthens the virus–T cell interaction through DBCO/azide bioorthogonal chemistry. The results show that the PEI‐DBCO/azide–glucose system effectively facilitates viral binding to T cells and elevates the transduction efficiency of the lentivirus from 20% to 80% without any effect on T cell proliferation and activity. More importantly, the PEI‐DBCO/azide–glucose system significantly doubles the yield of anti‐CD19 chimeric antigen receptor T (CAR‐T) cells and robustly boosts their antitumor capability compared to polybrene‐assisted lentiviral transduction both in vitro and in vivo. Overall, the bioorthogonal PEI‐DBCO/azide–glucose system significantly boosts viral transduction efficacy and exhibits a powerful gene‐manipulating capability in human primary T cells, thereby showing a great potential for clinical‐engineered T lymphocytes manufacture. [ABSTRACT FROM AUTHOR]