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In 2018, the FDA approved Patisiran (the siRNA therapeutic) for treating amyloidosis. Compared with traditional drugs, gene therapy can directly correct the disease-related genes at the genetic level, which guarantees a sustained effect. However, nucleic acids are unstable in circulation and have short half-lives. They cannot pass through biological membranes due to their high molecular weight and massive negative charges. To facilitate the delivery of nucleic acids, it is crucial to develop a suitable delivery strategy. The rapid development of delivery systems has brought light to the gene delivery field, which can overcome multiple extracellular and intracellular barriers that prevent the efficient delivery of nucleic acids. Moreover, the emergence of stimuli-responsive delivery systems has made it possible to control the release of nucleic acids in an intelligent manner and to precisely guide the therapeutic nucleic acids to the target site. Considering the unique properties of stimuli-responsive delivery systems, various stimuli-responsive nanocarriers have been developed. For example, taking advantage of the physiological variations of a tumor (pH, redox and enzymes), various biostimuli- or endogenous stimuli-responsive delivery systems have been fabricated to control the gene delivery processes in an intelligent manner. In addition, other external stimuli, such as light, magnetic fields and ultrasound, have also been employed to construct stimuli-responsive nanocarriers. Nevertheless, most stimuli-responsive delivery systems are in the preclinical stage, and some critical issues remain to be solved for advancing the clinical translation of these nanocarriers, such as the unsatisfactory transfection efficiency, safety issues, complexity of manufacturing and off-target effects. The purpose of this review is to elaborate the principles of stimuli-responsive nanocarriers and to emphasize the most influential advances of stimuli-responsive gene delivery systems. Current challenges of their clinical translation and corresponding solutions will also be highlighted, which will accelerate the translation of stimuli-responsive nanocarriers and advance the development of gene therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics15051450","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T01:37:09Z","timestamp":1683769029000},"page":"1450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Advances and Challenges of Stimuli-Responsive Nucleic Acids Delivery System in Gene Therapy"],"prefix":"10.3390","volume":"15","author":[{"given":"Meng","family":"Lin","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China"},{"name":"Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8264-0794","authenticated-orcid":false,"given":"Xianrong","family":"Qi","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.gene.2013.03.137","article-title":"History of gene therapy","volume":"525","author":"Wirth","year":"2013","journal-title":"Gene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.addr.2020.06.014","article-title":"Polymeric vehicles for nucleic acid delivery","volume":"156","author":"Kauffman","year":"2020","journal-title":"Adv. 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