15 years on siRNA delivery: Beyond the State-of-the-Art on inorganic nanoparticles for RNAi therapeutics (original) (raw)

RNAi Therapeutics: Current Status of Nanoncologic siRNA Delivery Systems

Journal of Bionanoscience, 2011

With the growing comprehensive understanding of antisense gene silencing and the mechanism of RNA interference (RNAi), small interfering RNA (siRNA) has gained tremendous attention as a putative therapeutic agent for cancer therapy and other diseases. Due to its inherent target specificity, siRNA has the potential to inhibit tumor cell proliferation, metastasis and retard tumor growth, all-the-while avoiding off-target and adverse effects that are commonly observed with conventional anti-cancer drugs. There are a few ongoing clinical trials using siRNA for cancer treatment and other diseases. However, to date, none have been approved by FDA. Crucial for clinical success, delivery reagents that promote cellular uptake of the siRNA, maintain its stability in the presence of nucleases and prevent potential immunogenicity in vivo are required. Therefore, in recent years, a wide range of siRNA delivery systems have been developed and evaluated. In this review, we describe the major strategies currently employed for siRNA delivery followed by a presentation of the most recent works using such a variety of delivery systems and carriers in different cancers.

Engineering RNA for Targeted siRNA Delivery and Medical Application

Advanced Drug Delivery Reviews, 2010

RNA engineering for nanotechnology and medical applications is an exciting emerging research field. RNA has intrinsically defined features on the nanometre scale and is a particularly interesting candidate for such applications due to its amazing diversity, flexibility and versatility in structure and function. Specifically, the current use of siRNA to silence target genes involved in disease has generated much excitement in the scientific community. The intrinsic ability to sequence-specifically downregulate gene expression in a temporally-and spatially controlled fashion has led to heightened interest and rapid development of siRNA-based therapeutics. Although methods for gene silencing have been achieved with high efficacy and specificity in vitro, the effective delivery of nucleic acids to specific cells in vivo has been a hurdle for RNA therapeutics. This article covers different RNA-based approaches for diagnosis, prevention and treatment of human disease, with a focus on the latest developments of non-viral carriers of siRNA for delivery in vivo. The applications and challenges of siRNA therapy, as well as potential solutions to these problems, the approaches for using phi29 pRNA-based vectors as polyvalent vehicles for specific delivery of siRNA, ribozymes, drugs or other therapeutic agents to specific cells for therapy will also be addressed.

Nanomaterials-Based siRNA Delivery: Routes of Administration, Hurdles and Role of Nanocarriers

Nanotechnology in Modern Animal Biotechnology, 2019

Ribonucleic acid interference (RNAi) is a potential alternative therapeutic approach to knock down the overexpression of genes in several disorders especially cancers with underlying genetic dysfunctions. For silencing of specific genes involved in cell cycle, small/short interfering ribonucleic acids (siRNAs) are being used clinically. The siRNA-based RNAi is more efficient, specific and safe antisense technology than other RNAi approaches. The route of siRNA administration for siRNA therapy depends on the targeted site. However, certain hurdles like poor stability of siRNA, saturation, off-target effect, immunogenicity, anatomical barriers and non-targeted delivery restrict the successful siRNA therapy. Thus, advancement of an effective, secure, and long-term delivery system is prerequisite to the medical utilization of siRNA. Polycationic nanocarriers mediated targeted delivery system is an ideal system to remove these hurdles and to increase the blood retention time and rate of intracellular permeability. In this chapter, we will mainly discuss the different biocompatible, biodegradable, non-toxic (organic, inorganic and hybrid) nanocarriers that encapsulate and shield the siRNA from the different harsh environment and provides the increased systemic siRNA delivery.

siRNA-based Nanoparticles for Cancer Therapy: Hurdles and Hopes

In recent times, profound advances in therapeutic strategies for cancer therapy have been made. Most of these strategies including cationic polymers, small molecule inhibitors and monoclonal antibodies originating from the bench have resulted in successful translations to the bedside. One of these remarkable strategies was the potential of small interfering RNA (siRNA) to regulate gene expression by RNA interference (RNAi). An avalanche of research has indeed proven that RNAi is extremely essential in cancer therapeutics, as well as a myriad of diseases. Their potential as therapeutic platforms however carry some limitations including delivery challenges, potential side effects, disturbance of intrinsic gene silencing mechanisms, and induction of the innate immune response. Some attempts have been made to overcome these challenges in order to improve the efficacy of RNAi-based therapeutics. Nanostructured entities (nanoparticles) and their formulations provide immense opportunities to substantially alter the treatment regimens, i.e. improving drug bioavailability, improving tissue permeability, and improving payload integrity. The objectives of this article are to (a) explain siRNA mechanism in the context of cancer therapy; (b) highlight the usefulness of nanoparticles-based delivery, and (c) review the prospects and challenges of the ongoing siRNA-based clinical research.

RNA nanomedicines: the next generation drugs?

Current opinion in biotechnology, 2016

RNA therapeutics could represent the next generation personalized medicine. The variety of RNA molecules that can inhibit the expression of any mRNA using, for example, RNA interference (RNAi) strategies, or increase the expression of a given protein using modified mRNA together with new gene editing strategies open new avenues for manipulating the fate of diseased cells while leaving healthy cells untouched. In addition, these therapeutic RNA molecules can maximize the treatment of diseases and minimize its adverse effects. Yet, the promise of RNA therapeutics is hindered by the lack of efficient delivery strategies to selectively target these molecules into specific cells. Herein, we will focus on the challenges and opportunities of the delivery of therapeutic RNAi molecules into cancer cells with special emphasis on solid tumors. Solid tumors represent more than 80 percent of cancers and some are very challenging to treat, not merely due to physiological barriers but also since t...

Biomaterials in siRNA Delivery: A Comprehensive Review

Advanced healthcare materials, 2016

With the dearth of effective treatment options for prominent diseases including Ebola and cancer, RNA interference (RNAi), a sequence-specific mechanism for genetic regulation that can silence nearly any gene, holds the promise of unlimited potential in treating illness ever since its discovery in 1999. Given the large size, unstable tertiary structure in physiological conditions and negative charge of small interfering RNAs (siRNAs), the development of safe and effective delivery vehicles is of critical importance in order to drive the widespread use of RNAi therapeutics into clinical settings. Immense amounts of time and billions of dollars have been devoted into the design of novel and diverse delivery strategies, and there are a handful of delivery systems that have been successfully translated into clinic. This review provides an introduction to the in vivo barriers that need to be addressed by siRNA delivery systems. We also discuss the progress up to the most effective and cl...

Nanoparticle-mediated systemic delivery of siRNA for treatment of cancers and viral infections

Theranostics, 2014

RNA interference (RNAi) is an endogenous post-transcriptional gene regulatory mechanism, where non-coding, double-stranded RNA molecules interfere with the expression of certain genes in order to silence it. Since its discovery, this phenomenon has evolved as powerful technology to diagnose and treat diseases at cellular and molecular levels. With a lot of attention, short interfering RNA (siRNA) therapeutics has brought a great hope for treatment of various undruggable diseases, including genetic diseases, cancer, and resistant viral infections. However, the challenge of their systemic delivery and on how they are integrated to exhibit the desired properties and functions remains a key bottleneck for realizing its full potential. Nanoparticles are currently well known to exhibit a number of unique properties that could be strategically tailored into new advanced siRNA delivery systems. This review summarizes the various nanoparticulate systems developed so far in the literature for...