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Perfluorocarbon Nanoemulsions for Combined Pulmonary siRNA Treatment of Lung Metastatic Osteosarcoma

Lung metastatic osteosarcoma is a lethal disease afflicting children and adolescents, with a 5‐year survival rate of less than 20%. The development of perfluorocarbon (PFC) nanoemulsions as systems for direct pulmonary delivery of combination drug/siRNA therapy is reported. Fluorinated polycation (F‐PCX) with an inherent ability to inhibit C‐X‐C receptor type 4 (CXCR4) is synthesized and used as a surfactant in the preparation of F‐PCX@PFC nanoemulsions. The nanoemulsions are loaded with siRNA against signal transducer and activator of transcription 3 (STAT3) for combined treatment of lung metastasis in osteosarcoma. Intratracheal instillation of the treatments significantly prolonged the survival of animals with established lung metastases. The treatment with F‐PCX@PFC/siSTAT3 emulsion polyplexes decreased the number of myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the tumors, while increasing CD8+ T cells infiltration and IFNγ secretion to overcome the immunosuppressive tumor microenvironment. The reported nanoemulsions represent a promising pulmonary treatment of lung metastatic osteosarcoma.