Stimulus-Responsive Nanodelivery and Release Systems for Cancer Gene Therapy: Efficacy Improvement Strategies

Huamin Zeng,1 Yiran Zhang,1,2 Ningyi Liu,1,3 Qingqing Wei,1,3 Fan Yang,1 Jie Li4 1Cancer Prevention and Treatment Institute of Chengdu, Department of Pathology, Chengdu Fifth People’s Hospital (The Second Clinical Medical College, Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, Sichuan, 611130, People’s Republic of China; 2School of Medical and Life Sciences, Chengdu University of traditional Chinese Medicine, Chengdu, Sichuan, 611137, People’s Republic of China; 3School of Basic Medicine, North Sichuan Medical College, Nanchong, Sichuan, 637007, People’s Republic of China; 4Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People’s Republic of ChinaCorrespondence: Jie Li, Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People’s Republic of China, Tel +86 183 0831 2997, Email kerald2lj@126.com Fan Yang, Cancer Prevention and Treatment Institute of Chengdu, Department of Pathology, Chengdu Fifth People’s Hospital (The Second Clinical Medical College, Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, Sichuan, 611130, People’s Republic of China, Tel +86 136 7819 2175, Email yangfan03@126.comAbstract: Introduction of exogenous genes into target cells to overcome various tumor diseases caused by genetic defects or abnormalities and gene therapy, a new treatment method, provides a promising strategy for tumor treatment. Over the past decade, gene therapy has made exciting progress; however, it still faces the challenge of low nucleic acid delivery and release efficiencies. The emergence of nonviral vectors, primarily nanodelivery and release systems (NDRS), has resulted in a historic breakthrough in the application of gene therapy. NDRS, especially stimulus-responsive NDRS that can respond in a timely manner to changes in the internal and external microenvironment (eg, low pH, high concentration of glutathione/reactive oxygen species, overexpressed enzymes, temperature, light, ultrasound, and magnetic field), has shown excellent loading and release advantages in the precision and efficiency of tumor gene therapy and has been widely applied. The only disadvantage is that poor transfection efficiency limits the in-depth application of gene therapy in clinical practice, owing to the presence of biological barriers in the body. Therefore, this review first introduces the development history of gene therapy, the current obstacles faced by gene delivery, strategies to overcome these obstacles, and conventional vectors, and then focuses on the latest research progress in various stimulus-responsive NDRS for improving gene delivery efficiency. Finally, the future challenges and prospects that stimulus-responsive NDRS may face in clinical application and transformation are discussed to provide references for enhancing in-depth research on tumor gene therapy.Keywords: stimulus-responsive NDRS, gene delivery, tumor treatment, delivery and release efficiency, tumor microenvironment, physiological barrier, efficacy improvement strategies