Nanoparticle-Based Follistatin Messenger RNA Therapy for Reprogramming Metastatic Ovarian Cancer and Ameliorating Cancer-Associated Cachexia

This study presents the first messenger RNA (mRNA) therapy for metastatic ovarian cancer and cachexia-induced muscle wasting based on lipid nanoparticles that deliver follistatin (FST) mRNA predominantly to cancer clusters following intraperitoneal administration. The secreted FST protein, endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with aggressive ovarian cancer and associated cachexia. By altering the cancer cell phenotype, mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors, and preserves muscle mass in cancer-bearing mice by inhibiting negative regulators of muscle mass. Finally, mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and counteracting muscle atrophy induced by chemotherapy and cancer-associated cachexia. The treated mice develop few nonadherent tumors that are easily resected from the peritoneum. Clinically, this nanomedicine-based mRNA therapy can facilitate complete cytoreduction, target resistance, improve resilience during aggressive chemotherapy, and improve survival in advanced ovarian cancer.

Automated summary

This study introduces a mRNA therapy for metastatic ovarian cancer and cachexia-induced muscle wasting, which utilizes lipid nanoparticles to deliver follistatin mRNA to cancer clusters. The therapy effectively reduces activin A levels associated with aggressive ovarian cancer and cachexia, preventing malignant ascites, delaying cancer progression, inducing solid tumor formation, and preserving muscle mass in cancer-bearing mice. The therapy also shows synergistic effects when combined with cisplatin, increasing mice survival and countering chemotherapy-induced muscle atrophy and cancer-associated cachexia.