Breaking Down Intracellular Barriers: Advanced Nanocarriers for Cytosolic Small-Interfering RNA Delivery

Nucleic-acid therapeutics are rapidly emerging as a transformative drug modality, capable of targeting pathogenic nucleic acids or proteins inside cells and thereby offering therapeutic potential. Although lipid nanoparticles have already delivered clinically approved small-interfering RNA and mRNA, the fraction of internalized cargo that ultimately reaches the cytosol remains disappointingly low, prompting intensive research to enhance intracellular delivery efficiency. This review provides a comprehensive analysis of the various intracellular barriers, including the plasma membrane, endolysosomal entrapment, degradation, and exocytic recycling, and critically examines state-of-the-art nanotechnology designed to overcome these hurdles. By integrating mechanistic insights with translational advances, we elaborate on rational design principles for the next generation of safe and reliable nanomedicines, which are expected to enhance the prospects of nucleic-acid therapeutics.