Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia

作者：Peng, Boya; Yang, Yuqi; Wu, Zhiyuan; Tan, Rachel; Pham, Thach Tuan; Yeo, Eric Yew Meng; Pirisinu, Marco; Jayasinghe, Migara Kavishka; Pham, Tin Chanh; Liang, Kun; Shyh-Chang, Ng^*; Le, Minh T. N.^*

来源：Molecular Therapy, 2023, 31(5): 1418-1436.

DOI：10.1016/j.ymthe.2023.03.036

• FATTY-ACID OXIDATION
• REVERSAL

Cancer cachexia is a multifactorial syndrome characterized by a significant loss of skeletal muscle, which negatively affects the quality of life. Inhibition of myostatin (Mstn), a negative regu-lator of skeletal muscle growth and differentiation, has been proven to preserve muscle mass in muscle atrophy diseases, including cachexia. However, myostatin inhibitors have repeat-edly failed clinical trials because of modest therapeutic effects and side effects due to the poor efficiency and toxicity of existing delivery methods. Here, we describe a novel method for deliv-ering Mstn siRNA to skeletal muscles using red blood cell -derived extracellular vesicles (RBCEVs) in a cancer cachectic mouse model. Our data show that RBCEVs are taken up by my-ofibers via intramuscular administration. Repeated intramus-cular administrations with RBCEVs allowed the delivery of siRNAs, thereby inhibiting Mstn, increasing muscle growth, and preventing cachexia in cancer-bearing mice. We observed the same therapeutic effects when delivering siRNAs against malonyl-CoA decarboxylase, an enzyme driving dysfunctional fatty acid metabolism in skeletal muscles during cancer cachexia. We demonstrate that intramuscular siRNA delivery by RBCEVs is safe and non-inflammatory. Hence, this method is useful to reduce the therapeutic dose of siRNAs, to avoid toxicity and off-target effects caused by systemic administration of naked siRNAs at high doses.

• 单位
  中国科学院