Therapeutic targeting of STAT3 with small interference RNAs and antisense oligonucleotides embedded exosomes in liver fibrosis

Abstract Hepatic fibrosis is a wound healing response that results in excessive extracellular matrix (ECM) accumulation in response to chronic hepatic injury. Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor associated with the pathogenesis of liver fibrosis. Though a promising potential therapeutic target, there are no specific drug candidates for STAT3. Exosomes are extracellular vesicles generated by all cell types with a capacity to efficiently enter cells across different biological barriers. Here, we utilize exosomes as delivery conduit to specifically target STAT3 in liver fibrosis. Exosomes derived from clinical grade fibroblast‐like mesenchymal stem cells (MSCs) were engineered to carry siRNA or antisense oligonucleotide (ASO) targeting STAT3 (iExo siRNA‐STAT3 or iExo mASO‐STAT3 ). Compared to scrambled siRNA control, siRNA‐STAT3, or ASO‐STAT3, iExo siRNA‐STAT3 or iExo mASO‐STAT3 showed enhanced STAT3 targeting efficiency. iExo siRNA‐STAT3 or iExo mASO‐STAT3 treatments suppressed STAT3 levels and ECM deposition in established liver fibrosis in mice, and significantly improved liver function. iExo mASO‐Stat3 restored liver function more efficiently when compared to iExo siRNA‐STAT3 . Our results identify a novel anti‐fibrotic approach for direct targeting of STAT3 with exosomes with immediate translational potential.