Cachexia is a debilitating syndrome that occurs in numerous diseases including cancer and is characterized by a significant loss of skeletal muscle mass (with or without fat loss) that cannot be reversed by nutritional support. It most commonly occurs in gastric (85% of patients), pancreatic (83%) and lung (61%) cancers and up to 30% of deaths in these patient populations are attributable to cachexia alone. The numerous clinical trials confirmed that wasting of skeletal muscle mass is the hallmark of cachexia and it is responsible for shorter survival, poor treatment outcomes, increased toxicity to chemotherapy, post-operative complications, and physical impairment. Despite all efforts, there are currently no effective therapies to prevent muscle wasting in cachectic patients. A multidisciplinary team of investigators with complementary expertise in drug delivery, gene therapy, and cancer cachexia will develop an effective treatment for cachexia-associated muscle wasting. It will be based on polymeric nanoparticles specifically designed to deliver follistatin messenger RNA (mRNA) to the liver cells after systemic administration. The delivered mRNA will direct the cellular machinery of the liver cells to produce follistatin, a secreted glycoprotein that is capable of increasing lean muscle mass through inhibition of myostatin and Activin A. The last two are growth differentiation factors whose serum concentrations are increased in cachectic states, and they play a critical role in negatively regulating muscle mass. The research team has already developed mRNA-loaded nanoplatform that is non-toxic and elevates serum levels of follistatin protein within 8 h after subcutaneous injection. Wild-type mice that were treated with the nanoplatform exhibited significant increases in lean body mass. To further advance this technology, the goals are: (i) to enhance the delivery of the already developed nanoparticles to the liver, (ii) to evaluate delivery efficiency of the nanoparticles in mice with the humanized liver, and (iii) to validate therapeutic efficacy of the nanoparticles in novel murine pancreatic ductal adenocarcinoma (PDAC) and lung cancer models that exhibit all the hallmark features of human cachexia. These goals will be addressed with the following Specific Aims: 1 Evaluate the efficiency of mRNA-loaded nanoparticles following intravenous administration. 2. Test nanoplatform in mice with the humanized liver. 3. Determine whether nanoparticle-mediated delivery of follistatin mRNA attenuates cachexia in mouse models of PDAC and lung cancer. At the completion of this project, the research team will produce strong evidence that the proposed therapy will preserve muscle mass and attenuate other features of cachexia in mice with pancreatic and lung cancers. The long-term impact of this project is the successful application of the novel treatment in medical practice to sufficiently limit death and suffering from various cancers including lung and pancreatic cancers.