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Review From Endocytosis to Nonendocytosis: The Emerging Era of Gene Delivery Jie Zhou, Zhentao Shao, Jia Liu, Qiao Duan, Xiang Wang, Juan Li, * and Huanghao Yang* Cite This: ACS Appl. Bio Mater. 2020, 3, 2686−2701 Read Online ACCESS Metrics More Article Recommendations . s e l c i ABSTRACT: Over the past two decades, gene therapy, as a promising way to t r a d regulate or replace abnormal gene, has made impressive progress with numerous e . h clinic trials. However, the success of gene therapy was hugely limited by its low ) s i C l T b translocation into cytoplasm. Therefore, technologies to efficiently protect and u U p ( e deliver therapeutic nucleic acids have been extensively investigated, but most of the 0 r 1 a delivery strategies involve endosomal entrapment, leading to low delivery efficiency. : h 7 s 3 y : l In this review, we discuss the latest advances in nonendocytosis-dependent strategies 6 e 0 t t a for delivering nucleic acids into cells. A highlight is provided on the cellular uptake a m i 1 t systems facilitated by the endosome−Golgi−endoplasmic reticulum pathway, pH low 2 i g 0 e insertion peptides, cell-penetrating peptides, scavenger receptor-mediated non- 2 l , o 8 t 1 endocytosis, membrane fusion, and the emerged thiol−disulfide exchange. The r w e o mechanisms