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

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 1 O 2 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.