Tumor suppression is a fundamental cellular process that prevents uncontrolled cell proliferation and tumorigenesis. However, the loss or inactivation of tumor suppressor mechanisms is a hallmark of cancer. Recent advances in C-based therapeutics have provided novel strategies to restore tumor-suppressive activity. Mimicking molecules such as TargomiRs and MRX34, alongside synthetic RNAs like MTL-CEBPA, are at the forefront of this therapeutic revolution. TargomiRs are engineered microRNA mimics that target oncogenic pathways, effectively reinstating the regulatory functions of tumor-suppressive microRNAs. MRX34, the first microRNA mimic to enter clinical trials, encapsulates miR-34a in liposomal nanoparticles, targeting key pathways involved in cell cycle regulation, apoptosis, and immune modulation. Meanwhile, MTL-CEBPA utilizes small activating RNAs (saRNAs) to upregulate CEBPA, a crucial transcription factor with tumor-suppressive roles in various cancers. These approaches demonstrate significant potential in preclinical and clinical settings, offering a pathway to overcome the challenges associated with targeting traditionally “undruggable” tumor suppressor genes. This chapter explores the mechanisms, therapeutic applications, and clinical progress of these RNA-based strategies, highlighting their promise in cancer treatment. By leveraging the precision and versatility of RNA therapeutics, these innovations pave the way for a new era in oncology, emphasizing the restoration of intrinsic tumor-suppressive functions.