Photothermal therapy (PTT) has received a lot of attention as a promising strategy for eliminating tumors quickly. However, the unavoidable inflammatory response during the treatment might result in a high concentration of M2-like tumor-associated macrophages (TAMs), increasing the risk of tumor recurrence and metastasis. To address this problem, gold-based nanocarriers (PGMP-small interfering RNA (siRNA) nanoparticles (NPs)) containing STAT6siRNA, that inhibited M2-like TAM polarization, were designed and investigated for PTT and gene therapy of non-small cell lung cancer (NSCLC). In an NSCLC model, the nanocarriers demonstrated excellent siRNA delivery ability and a high gene transfection rate of up to 90% in macrophages, thus inhibiting the polarization of about 87% of M2-like TAMs and effectively suppressing the invasion and metastasis of NSCLC. Meanwhile, the unique gold nanosphere structure offered improved PTT and contrast-enhanced ultrasound imaging, thus contributing to the efficient elimination and real-time monitoring of the tumor tissues. These nanocarriers with combined gene and photothermal therapeutic capabilities improved the efficacy of single-modality treatment, and showed the potential to inhibit cancer cell recurrence and metastasis to ultimately cure NSCLC.