<p>Lung cancer is a heterogeneous disease and the leading cause of cancer-related deaths worldwide. The aggressiveness of non-small-cell lung cancer (NSCLC) is often associated with oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway. Among the most prevalent mutations in NSCLC, epidermal growth factor receptor 1 (EGFR) and Kirsten rat sarcoma (KRAS) alterations play a key role in cancer progression and patient survival. In this study, we investigated the influence of EGFR and KRAS mutational status on the response to polycationic core–shell dendrimers, using NSCLC cell lines harboring different EGFR and KRAS profiles. Cells were treated with PURE_G4-OEI₄₈ and PURE_G4-OCEI₂₄ dendrimers, which showed heterogeneous responses. In PC-9^{<i>EGFREx19Del</i>} cells, PURE_G4-OEI₄₈ induced elevated p-ERK/ERK ratios, indicating activation of the ERK-MAPK pathway and resistance. Notably, the EGFR^Ex19Del mutation contributed to this resistance. To overcome this effect, a synergistic strategy combining PURE_G4-OEI₄₈ and PURE_G4-OCEI₂₄ with the tyrosine kinase inhibitor (TKI) gefitinib was explored. This combination sensitized PC-9 cells, reducing ERK activation and enhancing cell death. <i>Ex vivo </i>chick chorioallantoic membrane (CAM) assays confirmed that EGFR^Ex19Del drives resistance to PURE_G4-OEI₄₈, whereas co-treatment with gefitinib improves efficacy. The use of complex dendrimer systems allows precise modulation of membrane-targeted interactions and intracellular signaling, providing mechanistic insights into overcoming EGFR^Ex19Del-driven resistance. Overall, these findings highlight the translational potential of integrating membrane-targeted nanotherapeutics with EGFR-directed therapies to improve outcomes in NSCLC patients.</p>