Lung cancer is associated with very poor prognosis and considered one of the leading causes of death worldwide. Here, highly potent and selective biohybrid RNA interference (RNAi)-peptide nanoparticles (NPs) are presented that can induce specific and long-lasting gene therapy in inflammatory tumor associated macrophages (TAMs), via an immune modulation of the tumor milieu combined with tumor suppressor effects. The data here prove that passive gene silencing can be achieved in cancer cells using regular RNAi NPs. When combined with M2 peptide-based targeted immunotherapy that immuno-modulates TAMs cell population, a synergistic effect and long-lived tumor eradication can be observed along with increased mice survival. Treatment with low doses of siRNA (ED50 0.0025-0.01 mg kg(-1)) in a multi and long-term dosing system substantially reduces the recruitment of inflammatory TAMs in lung tumor tissue, reduces tumor size (approximate to 95%), and increases animal survival (approximate to 75%) in mice. The results here suggest that it is likely that the combination of silencing important genes in tumor cells and in their supporting immune cells in the tumor microenvironment, such as TAMs, will greatly improve cancer clinical outcomes.