Optimal delivery of RNA interference by viral vectors for cancer therapy

Abstract

In recent years, there has been a surge in the innovative modification and application of the viral vector-based gene therapy field. Significant and consistent improvements in the engineering, delivery, and safety of viral vectors have set the stage for their application as RNA interference (RNAi) delivery tools. Viral vector-based delivery of RNAi has made remarkable breakthroughs in the treatment of several debilitating diseases and disorders (e.g., neurological diseases); however, their novelty has yet to be fully applied and utilized for the treatment of cancer. This review highlights the most promising and emerging viral vector delivery tools for RNAi therapeutics while discussing the variables limiting their success and suitability for cancer therapy. Specifically, we outline different integrating and non-integrating viral platforms used for gene delivery, currently employed RNAi targets for anti-cancer effect, and various strategies used to optimize the safety and efficacy of these RNAi therapeutics. Most importantly, we provide great insight into what challenges exist in their application as cancer therapeutics and how these challenges can be effectively navigated to advance the field.

Keywords: AAV; AV; DNA viruses; HSV; RNA interference; RNA viruses; RNAi therapeutics; VSV; adeno-associated virus; adenovirus; cancer therapeutics; herpes simplex virus; integrating viruses; microRNA; non-replicating viruses; oncolytic viruses; replicating viruses; retroviruses; short hairpin RNA; silencing RNA; vesicular stomatitis virus; viral vectors.

Graphical abstract

Figure 1

Viruses as optimal vectors for RNA interference delivery A graphical depiction of the major sections of the review. The selection of different viral vectors is first outlined, which can broadly be divided into replication-incompetent vs. replication-competent vectors. Classification of RNA interference targets with anti-cancer effects are then summarized. Finally, strategies to optimize the safety and efficacy of these RNA-interference-expressing viral vectors is explored.

Figure 2

The therapeutic potential of RNAi species and their link to cancer therapy (Left) The delivery of microRNA by viral vectors can be divided into three major mechanisms of action: cell-death induction/direct tumor lysis, cellular process blockade, and drug sensitivity, each aiming to induce greater cell death and discourage neoplastic growth in the infected tumor cells. The endogenous and multi-targeting nature of microRNA gives delivery of this RNAi species tremendous versatility in cancer therapy. (Right) The delivery of shRNA/siRNA by viral vectors can be divided into four major mechanisms of action: immunomodulation, oncogene silencing, tumor proliferation and viability, and other inhibitory functions. If the correct gene is chosen, the strength of single gene knockdown by shRNA/siRNA can also confer profound anti-neoplastic activity in infected cancer cells. All targets listed have been experimentally demonstrated to confer therapeutic advantage in vivo over their respective unarmed virus controls.