As the second most common cancer and the first leading cause of cancer deaths, lung cancer attracts much research attention. Since cyclooxygenase-2 (COX-2) is overexpressing in nearly 80% of lung cancer patients, COX-2 inhibitors may benefit cancer patients via breaking the COX-2/arachidonic acid (AA)/ prostaglandin E2 (PGE2) axis, which is highly relevant to cancer progression. However, the COX-2 inhibitors fail to improve survival of cancer patients in clinical studies. To effectively take advantage of COX-2 overexpression in lung cancer, in this study, we advanced a novel strategy, instead of direct COX-2 inhibition, redirecting COX-2 catalyzed dihomo-γ-linolenic acid peroxidation by knocking down delta-5-desaturase (D5D) in lung cancer cells. We found that the D5D siRNA knockdown could repress the AA and PGE2 formation in lung cancer cells. While a distant free radical byproduct, 8-hydroxyoctanoic acid (8-HOA) was derived from DGLA by COX-2. Both exogenous 8-HOA and DGLA-derived endogenous 8-HOA resulted in inhibition of proliferation, survival, migration but activation of apoptosis in lung cancer cells. We believe that the inhibitory effect of 8-HOA lung cancer is possibly due to histone deacetylase (HDAC) and YAP1/TAZ inhibition. Additionally, we demonstrated the synergistic effect between 8-HOA and first-line chemo cisplatin on lung cancer. To improve the efficiency of D5D inhibition, we used innovative RNA nanotechnology to specifically deliver D5D siRNA to lung cancer in vitro and in vivo. The D5D siRNA was harbored by 3 way-junction (3WJ) RNA nanoparticle along with epithelial cell adhesion molecule (EpCAM) aptamer as targeting module, and Alexa 647 as imaging module. By using lung cancer and normal lung epithelial cell models, we demonstrated that 3WJ-EpCAM-D5D siRNA nanoparticles could suppress lung cancer cell growth by promoting 8-HOA formation in a COX-2 dependent manner. The EpCAM aptamer ensured the specific in vivo delivery of RNA nanoparticles to lung tumors, avoiding damage to other tissues and toxic/off-target effect. 3WJ-EpCAM-D5D siRNA nanoparticle significantly inhibited xenograft tumor growth in nude mice by regulating apoptosis, metastasis, and proliferation. Overall, our strategy generated an effective and safer outcome and paved the road to COX-2-based precise medicine for lung cancer therapy.