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

High Resolution Image Download MS PowerPoint Slide 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.