Neutrophil‐Targeting Semiconducting Polymer Nanotheranostics for NIR‐II Fluorescence Imaging‐Guided Photothermal‐NO‐Immunotherapy of Orthotopic Glioblastoma

Abstract Glioblastoma (GBM) is one of the deadliest primary brain tumors, but its diagnosis and curative therapy still remain a big challenge. Herein, neutrophil‐targeting semiconducting polymer nanotheranostics (SSPN iNO ) is reported for second near‐infrared (NIR‐II) fluorescence imaging‐guided trimodal therapy of orthotopic glioblastoma in mouse models. The SSPN iNO are formed based on two semiconducting polymers acting as NIR‐II fluorescence probe as well as photothermal conversion agent, respectively. A thermal‐responsive nitric oxide (NO) donor and an adenosine 2A receptor (A2AR) inhibitor are co‐integrated into SSPN iNO to enable trimodal therapeutic actions. SSPN iNO are surface attached with a neutrophil‐targeting ligand to mediate their effective delivery into orthotopic GBM sites via a “Trojan Horse” manner, enabling high‐sensitive NIR‐II fluorescence imaging. Upon NIR‐II light illumination, SSPN iNO effectively generates heat via NIR‐II photothermal effect, which not only kills tumor cells and induces immunogenic cell death (ICD), but also triggers controlled NO release to strengthen tumor ICD. Additionally, the encapsulated A2AR inhibitor can modulate immunosuppressive tumor microenvironment by blocking adenosine‐A2AR pathway, which further boosts the antitumor immunological effect to observably suppress the orthotopic GBM progression. This study can provide a multifunctional theranostic nanoplatform with cumulative therapeutic actions for NIR‐II fluorescence imaging‐guided effective GBM treatment.