Therapeutic targeting of STAT3 with small interference RNAs and antisense oligonucleotides embedded exosomes in liver fibrosis.
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 (iExosiRNA-STAT3 or iExomASO-STAT3 ). Compared to scrambled siRNA control, siRNA-STAT3, or ASO-STAT3, iExosiRNA-STAT3 or iExomASO-STAT3 showed enhanced STAT3 targeting efficiency. iExosiRNA-STAT3 or iExomASO-STAT3 treatments suppressed STAT3 levels and ECM deposition in established liver fibrosis in mice, and significantly improved liver function. iExomASO-Stat3 restored liver function more efficiently when compared to iExosiRNA-STAT3 . Our results identify a novel anti-fibrotic approach for direct targeting of STAT3 with exosomes with immediate translational potential.
['Tang|Min|M|', 'Chen|Yang|Y|', 'Li|Bingrui|B|', 'Sugimoto|Hikaru|H|', 'Yang|Sujuan|S|', 'Yang|Changqing|C|', 'LeBleu|Valerie S|VS|', 'McAndrews|Kathleen M|KM|', 'Kalluri|Raghu|R|']
D000818:Animals D002251:Carbon Tetrachloride D055354:Exosomes D005260:Female D005786:Gene Expression Regulation D008103:Liver Cirrhosis D051379:Mice D008807:Mice, Inbred BALB C D016376:Oligonucleotides, Antisense D034741:RNA, Small Interfering D050796:STAT3 Transcription Factor D015398:Signal Transduction
STAT3 liver fibrosis engineered exosomes mesenchymal stromal cells