TME-Responsive Multistage Nanoplatform for siRNA Delivery and Effective Cancer Therapy

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 clinical or preclinical treatment of various diseases including cancer. Small interfering RNA (siRNA) is the effector molecule of RNAi technology. However, as polyanionic macromolecules, naked siRNAs have a short circulatory half-life (<15 min) and is rapidly cleared by renal filtration, which greatly hinders their clinical application. Furthermore, the anionic and macromolecular characteristics of naked siRNAs impede their readiness to cross the cell membrane and therefore delivery vehicles are required to facilitate the cellular uptake and cytosolic delivery of naked siRNAs. In the past decade, numerous nanoparticles (NPs) such as liposomes have been employed for in vivo siRNA delivery, which have achieved favorable therapeutic outcomes in clinical disease treatment. In particular, because tumor microenvironment (TME) or tumor cells show several distinguishing biological/endogenous factors (eg, pH, enzymes, redox, and hypoxia) compared to normal tissues or cells, much attention has recently paid to design and construct TME-responsive NPs for multistaged siRNA delivery, which can respond to biological stimuli to achieve efficient in vivo gene silencing and better anticancer effect. In this review, we summarize recent advances in TME-responsive siRNA delivery systems, especially multistage delivery NPs, and discuss their design principles, functions, effects, and prospects.