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Background <p>Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered as classic targeted drugs for <i>EGFR</i>-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.</p> Methods <p>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 <sup>1</sup>O<sub>2</sub> through the efficient chemodynamic therapy (CDT) and sonodynamic therapy (SDT), triggering intense ER stress. Meanwhile, the released <i>YAP</i>-siRNA interfered with the expression of YAP and the <i>EGFR</i> bypass signaling pathway, reversing the AXL-mediated resistance to EGFR-TKI.</p> Results <p>Furthermore, significant glucose consumption and ER stress triggered the immunogenic cell death (ICD) and systemic immune activation, and down-regulated the <i>PERK-Nrf2</i> signaling pathway and multidrug resistance protein (MRP1).</p> Conclusion <p>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.</p> Graphical Abstract <p></p>

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Nanoplatforms for EGFR-TKI resistance reversion and immunoactivation in NSCLC by ER stress and siRNA intervention

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • 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

摘要

Background

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.

Methods

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.

Results

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).

Conclusion

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.

Graphical Abstract