2. Academic Validation
  3. Targeting RRM2 with dual-modal theranostic smart nanoresponder overcomes osimertinib resistance and triggers immune remodeling in NSCLC

Targeting RRM2 with dual-modal theranostic smart nanoresponder overcomes osimertinib resistance and triggers immune remodeling in NSCLC

  • Sci Adv. 2025 Oct 17;11(42):eady7930. doi: 10.1126/sciadv.ady7930.
Jinyu Zhu 1,  Kaihui Cui 2,  Wenyuan Zhou 1,  Xin Zhou 1,  Yuan Yao 1,  Chuanke Zhao 3,  Yuwen Yang 1,  Yang Liu 1,  Jinping Tao 1,  Zhi Yang 1,  Hua Zhu 1,  Bufu Tang 4 5,  Nan Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 2 Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
  • 3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 4 Department of Interventional Radiology, Zhongshan hospital, Shanghai Institute of Medical Imaging, Shanghai Institution of Medical Imaging, Shanghai, National Clinical Research Center of Interventional Medicine, Fudan University, Shanghai 200032, China.
  • 5 Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, Lishui 323000, China.
PMID: 41105786 DOI: 10.1126/sciadv.ady7930
Abstract

Osimertinib (Osi) resistance limits its efficacy in EGFR-mutant non-small cell lung Cancer (NSCLC). Here, we developed a pH-responsive cationic nanovesicle (124I/Cy5.5-sO@FCLs), equipped with dual-modal positron emission tomography (PET) and fluorescence imaging capabilities, to enable dynamic monitoring of the role of ribonucleotide reductase M2 subunit (RRM2) disruption in overcoming Osi resistance and enhance targeted Anticancer efficacy in NSCLC. RRM2 was identified as a critical driver of poor prognosis and Osi resistance in NSCLC. The 124I/Cy5.5-sO@FCLs enabled real-time tracking of tumor targeting and biodistribution, and CRISPR-Cas9-mediated RRM2 disruption efficiently reversed Osi resistance and potentiated synergistic Anticancer effects, which was attributed to counteracting TGF-β/SMAD2/3-mediated epithelial-mesenchymal transition (EMT) and amplifying cGAS/STING-induced Ferroptosis. Furthermore, the nanovesicles triggered STING-dependent immunogenic cell death (ICD), stimulating tumor infiltration of dendritic cells (DCs) and T cells; combination with anti-PD-L1 therapy augmented NSCLC regression. Collectively, 124I/Cy5.5-sO@FCLs integrate gene editing with targeted therapies while enabling dynamic, quantitative monitoring, providing an approach for precision-targeted treatment in Osi-resistant NSCLC.

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