Yes-associated protein (YAP) has been identified as a key driver for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance. Inhibition of YAP expression could be a potential therapeutic option for treating non-small-cell lung cancer (NSCLC). Herein, a nanococktail therapeutic strategy is proposed by employing amphiphilic and block-dendritic-polymer-based nanoparticles (NPs) for targeted co-delivery of EGFR-TKI gefitinib (Gef) and YAP-siRNA to achieve a targeted drug/gene/photodynamic therapy. The resulting NPs are effectively internalized into Gef-resistant NSCLC cells, successfully escape from late endosomes/lysosomes, and responsively release Gef and YAP-siRNA in an intracellular reductive environment. They preferentially accumulate at the tumor site after intravenous injection in both cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of Gef-resistant NSCLC, resulting in potent antitumor efficacy without distinct toxicity after laser irradiation. Mechanism studies reveal that the cocktail therapy could block the EGFR signaling pathway with Gef, inhibit activation of the EGFR bypass signaling pathway via YAP-siRNA, and induce tumor cell apoptosis through photodynamic therapy (PDT). Furthermore, this combination nanomedicine can sensitize PDT and impair glycolysis by downregulating HIF-1α. These results suggest that this stimuli-responsive dendritic-polymer-based nanococktail therapy may provide a promising approach for the treatment of EGFR-TKI resistant NSCLC.
Keywords: EGFR-TKI; dendritic polymer drug delivery; drug resistance; non-small-cell lung cancer; yes-associated protein.
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