Abstract
Since the discovery of RNA interference (RNAi), RNAi technology has rapidly developed into an efficient tool for post-transcriptional gene silencing, which has been widely used for gene function analysis and clinical or preclinical treatment of various diseases (e.g., malignant tumor, Hepatitis B, obesity, andmultiple neuropathy). Small interfering RNA (siRNA) is the effector molecule of RNAi technology. As a biological macromolecule with negative charges, naked siRNA has a short half-life in vivo , and is easily attacked by nucleases and filtered by glomeruli. Therefore, the clinical application of naked siRNA is significantly limited. The key challenge for clinical translation of RNAi technology is to construct safe and efficient delivery carriers to improve the siRNA stability in vivo and gene silencing efficacy in target cells. Currently, numerous nanocarriers such as liposomes have been employed for in vivo siRNA delivery, which have achieved favorable therapeutic outcomes in clinical or preclinical disease treatment. It has been demonstrated that solid tumors show specific vascular structures and physiological microenvironment (e.g., weakly acidic environment, hypoxia, over-expression of specific chemicals and enzymes). Based on this fact, researches have recently paid great attention to designing and constructingtumor microenvironment (TME)-responsive nanocarriers to improve the accumulation of siRNA in tumor sites and enhance gene silencing in tumor cells. In this review, we summarize the design principles and functional characteristics of recently developed TME-responsive siRNA delivery nanocarriers, analyze their advantages and disadvantages, and explore the development trend of TME-responsive siRNA delivery nanocarriers in the future.
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