Targeted RNA Degradation via LipoSM-RiboTAC Nanoparticles: A Versatile Platform for Cancer Therapy

RNA molecules play critical roles in various diseases by regulating transcription, translation, and protein expression at the genetic level, positioning RNA-targeted therapeutics as a transformative frontier in precision medicine. Ribonuclease-targeting chimeras (RiboTAC) have emerged as a promising modality by leveraging endogenous RNases (e.g., RNase L) for RNA degradation, offering superior pharmacokinetics, enhanced specificity, and sustained therapeutic effects compared to conventional approaches. Despite their potential, conventional RiboTAC development remains constrained by laborious screening processes and structural complexity, limiting its clinical translation. In this study, we first proposed split-and-mix-RiboTAC based on liposome self-assembly (LipoSM-RiboTAC) to achieve RNA degradation for cancer therapy. This self-adjustable platform possesses self-optimized biomolecule spatial recognition for facile screening, with rapid cellular internalization, robust activation of endogenous RNase L, and precise degradation of oncogenic RNAs. Collectively, we have established an efficient and low-toxicity platform for targeted RNA degradation, which holds promise for cancer therapy and offers novel insights into precision gene therapy.