Bioreducible polymers for gene silencing and delivery.

Polymeric gene delivery vectors show great potential for the construction of the ideal gene delivery system. These systems harness their ability to incorporate versatile functional traits to overcome most impediments encountered in gene delivery: from the initial complexation to their target-specific release of the therapeutic nucleic acids at the cytosol. Among the numerous multifunctional polymers that have been designed and evaluated as gene delivery vectors, polymers with redox-sensitive (or bioreducible) functional domains have gained great attention in terms of their structural and functional traits. The redox environment plays a pivotal role in sustaining cellular homeostasis and natural redox potential gradients exist between extra- and intracellular space and between the exterior and interior of subcellular organelles. In some cases, researchers have designed the polymeric delivery vectors to exploit these gradients. For example, researchers have taken advantage of the high redox potential gradient between oxidizing extracellular space and the reducing environment of cytosolic compartments by integrating disulfide bonds into the polymer structure. Such polymers retain their cargo in the extracellular space but selectively release the therapeutic nucleic acids in the reducing space within the cytosol. Furthermore, bioreducible polymers form stable complex with nucleic acids, and researchers can fabricate these structures to impart several important features such as site-, timing-, and duration period-specific gene expression. Additionally, the introduction of disulfide bonds within these polymers promotes their biodegradability and limits their cytotoxicity. Many approaches have demonstrated the versatility of bioreducible gene delivery, but the underlying biological rationale of these systems remains poorly understood. The process of disulfide reduction depends on multiple variables in the cellular redox environment. Therefore, the quest to unravel various issues such as the site and time of disulfide bond reduction during the cellular uptake and trafficking have stimulated a number of interesting studies which have employed disulfide compounds with a variety of reducible linkers. Such studies help researchers understand not only how modifications made to disulfides can alter their thiol-disulfide exchange characteristics but also to decipher the effect of the induced changes on the dynamics of the redox environment. This Account discusses current research trends and recent progress in the disulfide chemistry enabling novel and versatile designs of reducible polymeric gene delivery systems. We present strategies for the introduction of disulfide bonds into polymers. These representative examples and their respective outcomes elaborate the benefit and efficiency of disulfides at the individual stages of gene delivery.