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.