Authors
Yingshan Qu, Yuping Jiang, Zhenzhen Zhu, Yi Dai, Wenqiao Wang, Zhaohui Li, Lina Ma, Yingming Sun, Danping Liu, Yan Ma, Wei Han, Wenhua Xu, Jinsheng Shi, Xiaoying Kong
Published in
Journal of nanobiotechnology. Jul 03, 2026. Epub Jul 03, 2026.
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered as classic targeted drugs for EGFR-mutated non-small cell lung cancer (NSCLC), but induce EGFR-TKI-resistance and immunosuppression at advanced stage. The targeted inhibition of YES-associated proteins (YAP) combined with immunomodulation is expected to be a distinctive supplementary approach for EGFR-TKI-resistant NSCLC therapy.
Herein an endoplasmic reticulum (ER)-targeting Zn/Cu-bi-single-atom nanoplatform (Zn/Cu-BSRGT) was prepared for EGFR-TKI resistance reversion, cascaded ER stress and immunoactivation. Specifically, after precisely targeting to the ER, Zn/Cu-BSRGT NPs provided simultaneous release of ·OH and 1O2 through the efficient chemodynamic therapy (CDT) and sonodynamic therapy (SDT), triggering intense ER stress. Meanwhile, the released YAP-siRNA interfered with the expression of YAP and the EGFR bypass signaling pathway, reversing the AXL-mediated resistance to EGFR-TKI.
Furthermore, significant glucose consumption and ER stress triggered the immunogenic cell death (ICD) and systemic immune activation, and down-regulated the PERK-Nrf2 signaling pathway and multidrug resistance protein (MRP1).
In summary, the combined application of single-atom-nanozyme catalytic technology and gene-targeted silencing technology successfully reversed EGFR-TKI resistance and promoted immunoactivation in NSCLC under ER-targeting assistance, providing support for the new strategic development of drug-resistant NSCLC.
PMID:
42399915
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.
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