Rekindling RNAi Therapy: Materials Design Requirements for In Vivo siRNA Delivery

Abstract

<p class="first" id="P1">With the recent FDA approval of the first siRNA-derived therapeutic, RNA interference (RNAi)-mediated gene therapy is undergoing a transition from research to the clinical space. The primary obstacle to realization of RNAi therapy has been the delivery of oligonucleotide payloads. This review aims to identify and describe key design features needed for nanoscale vehicles to achieve effective delivery of siRNA-mediated gene silencing agents <i>in vivo</i>. We break the problem into three elements: (1) protection of siRNA from degradation and clearance; (2) selective homing to target cell types; and (3) cytoplasmic release of the siRNA payload by escaping or bypassing endocytic uptake. The <i>in vitro</i> and <i>in vivo</i> gene silencing efficiency values that have been reported in publications over the past decade are quantitatively summarized by material type (lipid, polymer, metal, mesoporous silica, and porous silicon), and the overall trends in research publication and in clinical translation are discussed to reflect on the direction of the RNAi therapeutics field. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/9aa59926-8aee-4702-83d3-66421baa4308/PubMedCentral/image/nihms-1053425-f0001.jpg"/> </div> </p><p id="P3">RNA interference-mediated therapy has been researched for the past 20 years, but has suffered from lack of effective oligonucleotide-delivery systems. With advancements in nanoparticle design, the first siRNA-based formulation was FDA-approved in 2018. This review discusses the challenges in <i>in vivo</i> RNAi and materials design requirements to overcome them. Recent trends in research and clinical translation are also discussed. </p>