Unleashing the power of nucleic acid therapeutics through efficient cytosolic delivery

The approval of siRNA-based therapy for liver disease in 2018 and the subsequent success of mRNA-based SARS-CoV-2 vaccines have inaugurated a new era in nucleic acid-based therapeutics. These breakthroughs underscore the transformative potential of nucleic acid-based therapeutics, which modulate gene function, correct genetic defects, or disrupt pathological molecular processes. Such advances represent a paradigm shift in modern medicine. Despite their immense promise, the clinical realization of nucleic acid-based therapies is fundamentally constrained by endosomal entrapment, a critical barrier that significantly limits therapeutic efficacy. Overcoming this obstacle is imperative to fully unlock the potential of these therapies. Designing effective strategies to facilitate the escape of nucleic acids from endosomes-or bypassing endosomal pathways altogether-remains a central challenge in the field. In this review, we provide a comprehensive and critical analysis of current approaches aimed at enhancing endosomal escape or circumventing endosomal entrapment. By highlighting both the successes and limitations of these strategies, we aim to offer valuable insights to inform the development of more efficient and clinically viable nucleic acid delivery systems, advancing the future of molecular medicine.