A comprehensive update of siRNA delivery design strategies for targeted and effective gene silencing in gene therapy and other applications

ABSTRACT

Introduction

RNA interference (RNAi) using small interfering RNA (siRNA) is a promising strategy to control many genetic disorders by targeting the mRNA of underlying genes and degrade it. However, the delivery of siRNA to targeted organs is highly restricted by several intracellular and extracellular barriers.

Areas covered

This review discusses various design strategies developed to overcome siRNA delivery obstacles. The applied techniques involve chemical modification, bioconjugation to specific ligands, and carrier-mediated strategies. Nanotechnology-based systems like liposomes, niosomes, solid lipid nanoparticles (SLNs), dendrimers, and polymeric nanoparticles (PNs) are also discussed.

Expert opinion

Although the mechanism of siRNA as a gene silencer is well-established, only a few products are available as therapeutics. There is a great need to develop and establish siRNA delivery systems that protects siRNAs and delivers them efficiently to the desired sitesare efficient and capable of targeted delivery. Several diseases are reported to be controlled by siRNA at their early stages. However, their targeted delivery is a daunting challenge.

KEYWORDS:

• Small interfering RNA (siRNA)
• nanotechnology
• bioconjugation
• chemical modification
• gene delivery
• gene therapy
• drug delivery
• gene silencing
• targeted gene delivery

Article highlights

• siRNA therapeutics are designed to degrade targeted mRNAs, blocking the expression.

• The therapeutic efficacy of siRNA is challenged by numerous intracellular and extracellular barriers, resulting in rapid clearance of siRNA from systemic circulation.

• Modifications of naked siRNA molecules have the potential to increase their resistance to degradation by endonucleases, prolong their circulation time, and penetrate barriers.

• The conjugation of siRNA therapies to specific ligands has emerged as a leading strategy to direct siRNA to specific sites of action.

• Nano-based drug delivery systems such as liposomes, niosomes, SLNs, PNs, and dendrimers may optimize the delivery of naked siRNA therapeutics for effective targeting and gene silencing in gene therapy and other applications.

This box summarizes key points discussed in the article.

Declaration of interest

A Abosalha is funded by a full scholarship from the Ministry of Higher Education of the Arab Republic of Egypt. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript is supported by the Canadian Institutes of Health Research [# 20193PJT-420512 a].