Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) was one of the main drugs in the treatment of non-small cell lung cancer (NSCLC). Previous studies had demonstrated that PDZ and LIM Domain 5 (PDLIM5) played an important role in EGFR TKIs resistance. However, there was no feasible method to eliminate EGFR TKIs resistance by suppressing this gene. Here, we formulated a novel mesoporous silica-loaded PDLIM5 siRNA (Small interfering RNA) nanoplatforms. The results have shown that PDLIM5 siRNA could be effectively bound to the nanoplatforms and had good biocompatibility. Further exploration suggested that the nano-platform combined with ultrasonic irradiation could be very effective for siRNA delivery and ultrasound imaging. Moreover, Epithelial-mesenchymal transformation (EMT) changes occurred in PC-9 Gefitinib resistance (PC-9/GR) cells during the development of drug resistance. When PDLIM5 siRNA entered PC-9/GR cells, the sensitivity of drug-resistant cells to gefitinib could be restored through the transforming growth factor-β (TGF-β)/EMT pathway. Therefore, PDLIM5 may be an important reason for the resistance of NSCLC cells to gefitinib, and this nanoplatform may become a novel treatment for EGFR TKIs resistance in NSCLC patients.