From Endocytosis to Nonendocytosis: The Emerging Era of Gene Delivery

Over the past two decades, gene therapy, as a promising way to regulate or replace abnormal gene, has made impressive progress with numerous clinic trials. However, the success of gene therapy was hugely limited by its low translocation into cytoplasm. Therefore, technologies to efficiently protect and deliver therapeutic nucleic acids have been extensively investigated, but most of the delivery strategies involve endosomal entrapment, leading to low delivery efficiency. In this review, we discuss the latest advances in nonendocytosis-dependent strategies for delivering nucleic acids into cells. A highlight is provided on the cellular uptake systems facilitated by the endosome-Golgi-endoplasmic reticulum pathway, pH low insertion peptides, cell-penetrating peptides, scavenger receptor-mediated nonendocytosis, membrane fusion, and the emerged thiol-disulfide exchange. The mechanisms, pros, and cons of these systems are discussed. Finally, current challenges and future perspectives for the translation of nonendocytic gene delivery vectors, especially thiol-mediated cellular uptake, into clinical applications are discussed.