Tumor Extracellular Vesicles lncOSLMT Drives Lung Inflammatory Premetastatic Niche Formation in Osteosarcoma via m ⁶ A‐Dependent hnRNPA2B1/COX‐2 Axis

ABSTRACT Tumor‐derived extracellular vesicles (EVs) play critical roles in premetastatic niche (PMN) formation. Here, we demonstrated that EVs from highly metastatic osteosarcoma cell lines preferentially localized to lung fibroblasts and induce inflammatory PMN formation. High‐throughput profiling of EVs‐derived long noncoding RNAs (lncRNAs) identified lncOSLMT as a candidate enriched in EVs and markedly upregulated in patient tumors and serum, with elevated levels correlating with poor prognosis. Mechanistically, in EVs, lncOSLMT directly bound the RNA‐binding protein hnRNPA2B1. Following internalization by recipient lung fibroblasts, hnRNPA2B1 bound to N ⁶ ‐methyladenosine (m ⁶ A) ‐modified sites in the 3’UTR of PTGS2 mRNA, leading to transcript stabilization and increased COX‐2 expression. For therapeutic intervention, we developed lactoferrin‐resveratrol (LF‐RES) nanoparticles, which loaded siRNA against lncOSLMT. Intravenous administration of LF‐RES‐siRNA in mice reduced EVs‐induced lung inflammation and suppressed lung metastasis. Combination with EP2/EP4 antagonists produced enhanced anti‐metastatic effects. These findings establish EVs‐derived lncOSLMT as a key regulator of inflammatory PMN formation in the lung and highlight the potential of LF‐RES‐siRNA nanoparticles as a targeted anti‐metastatic therapy in osteosarcoma.