NIR-II Nanomedicine Engineered CAR-NK Cells for Precision Navigation and Potentiating Lung Cancer Immunotherapy by Remodeling Tumor Microenvironment.

Despite the prominent success against hematologic malignancies in clinical settings, chimeric antigen receptor NK (CAR-NK) cell immunotherapy is still hindered in lung cancer tumors owing to insufficient infiltration and poor immune activation induced by the immunosuppressive tumor microenvironment (TME). Herein, a nanoengineered CAR-NK biohybrid (CK-PSI) was constructed by conjugating nanomedicine (PSI NPs) containing a near-infrared II (NIR-II) polymer and a specific small-molecule inhibitor of Smad3 (SIS3) to the surface of metabolic glycan-engineered CAR-NK cells via a bioorthogonal reaction. Anti-B7H3 CAR modification on cell vectors offers selectively targeted delivery of hitchhiking NIR-II nanomedicine into lung cancer tumors, simultaneously enabling real-time tracking of CAR-NK cells and precise localization of deep-seated tumors through NIR-II fluorescence imaging. NIR-II excitation mild photothermal therapy not only destroys tumor cells by thermal ablation but also promotes the infiltration and penetration of CK-PSI through the rupture of physical barriers within tumor tissues. More importantly, the in situ release of the Smad3 inhibitor further reduces extracellular matrix (ECM) deposition through TGF-β signaling pathway blockade in the TME, thereby boosting the infiltration and immune activation of CAR-NK cells. The bioorthogonal nanohybrid with NIR-II phototheranostic triggered cell localization and immunomodulatory capabilities provides a new paradigm for potentiating the infiltration and immune activation efficiency of CAR-NK cells against solid tumors.