Elsevier

Drug Discovery Today

Volume 27, Issue 5, May 2022, Pages 1431-1440
Drug Discovery Today

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Role of siRNA-based nanocarriers for the treatment of neurodegenerative diseases

https://doi.org/10.1016/j.drudis.2022.01.003Get rights and content

Highlights

  • The clinical application of siRNA for brain disease therapy remains a big challenge.

  • The siRNA based gene silencing technology has proven potential for treatment of NDs.

  • Nanocarriers can provide promising opportunities for improving NDs.

  • We highlighted the role of nanocarriers for the treatment of NDs.

Abstract

Neurodegenerative disorders (NDs) lead to the progressive degeneration of the structural and physiological functions of the central and peripheral nervous systems, resulting in lifelong cognitive and motor dysfunction. Although comprehensive treatment of NDs is lacking, small interfering (si)RNA has shown therapeutic utility in the form of cellular nuclease-driven downregulation of mRNA levels. Various nanotechnologies have been used to modulate crucial physicochemical and biopharmaceutical properties of siRNA to provide protection and to enhance biomembrane interactions, residence times, tissue absorption, and cellular internalization for improved cytoplasm and/or nucleus interactions. In this review, we highlight advances in, and the role of, siRNA-based nanocarriers for the treatment of various NDs.

Introduction

‘ND’ refers to a range of partly inherited conditions characterized by progressive damage to neurons in the brain as a result of the development, progression, and establishment of disease features. Given the degradation of neurons and their inability to replicate or repair themselves, NDs are often incurable and result in permanent memory and motor function dysfunction. The incidence of NDs imposes huge medical and financial burdens on healthcare systems worldwide, and occur mainly in those above 60 years of age. With a rapidly increasing older population worldwide, the occurrence and prevalence of NDs, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are also increasing, requiring active interventions for the effective management of the most common NDs.

The field of nanomedicine deals with the optimal use of nano conduits with a 10–100-nm particle size range to aid disease diagnosis and drug delivery to meet therapeutic treatment goals. Nanomaterials can be used as therapeutic moieties, drug carriers, scaffolds, and for molecular imaging of disease progression and treatment.1., 2. The field of application for nanocarriers is vast owing to properties attributed to their smaller particle size, high surface area, ultradeformability, transformable shapes and sizes, specific surface characteristics, and ultratunable chemical and biological reactivity. The increased surface area of nanocarriers results in an enormous adsorption capacity, which allows loading of various genetic materials, synthetic compounds/drug precursors, trace elements, and biomolecules, such as proteins, thus improving site-specific targeting and disease treatment. The blood–brain barrier (BBB) is a crucial factor guiding the delivery of drugs to the brain. It restricts the free movement of most bio- and/or synthetic molecules into and out of the brain because of its intrinsic role to stop uncontrolled external invasion and ensure the protection of the central nervous system (CNS). However, many studies have been performed to circumvent this defensive barrier with minimal and reversible alterations to the BBB integrity.3 To date, several nanomaterials have been investigated for various neurological disorders and tumors, including polymeric nanoparticles (NPs), polymeric micelles, metallic NPs, liposomes, and carbon-based nanosystems, such as quantum dots (QDs) and carbon nanotubes (CNTs). Although there is room for improvement, most have shown promising results and immense utility in terms of their clinical relevance. Liposomal vincristine, liposomal irinotecan, PEGylated IFN-β1a, and PEGylated factor VIII are examples of nanotechnology-based drug delivery systems that have been approved by the US Food and Drug Administration (FDA), with some of these nanosystems in clinical trials for human use.4 Thus, there is significant potential for such approaches to transition from the laboratory to the clinic.

Since the 1990s, research has focused on overcoming the issues and limitations associated with nanocarriers in terms of their therapeutic applications in NDs. Lipid carriers, such as liposomes, nanostructured lipid carriers (NLCs), solid lipid NPs (SLNs), drug–phospholipid complexes, polymeric nanocarriers (e.g., dendrimers, nanocapsules, nanoparticulate systems, and nanocrystals), micellar systems, and inorganic nanomaterials are widely used for the delivery of drugs against NDs owing to their biocompatibility and potential to cross biological barriers.5 Nanocarriers are considered more advantageous than several conventional drug delivery approaches because of their unique ability to cross the BBB, ligand-mediated targeting, and slow or controlled release of the drugs. For example, poly(lactic-co-glycolic acid) (PGLA)-based polymeric nanocarriers were tested for the prolonged, sustained release of neurotrophic factors and levodopa for the treatment of PD. Carbon nanotubes, gold NPs (AuNPs), and other nanomaterial systems are being developed with an acceptable size and shape with higher stability and ease for use as diagnostics in molecular imaging. For example, the higher BBB permeability of AuNPs is correlated with their shape (spherical) and size (20 nm).6 In a recent study, dopamine increased Raman scattering from the surface of AuNPs, allowing researchers to evaluate levels of dopamine in the brain. Recent research trends highlight the utility of nanocarriers in neuroimaging and drug delivery to the brain by tailoring the hydrophobic–hydrophilic balance to the size and shape of the nanocarriers, enabling them to cross the BBB. Although the BBB limits the effectiveness of oral or intravenous delivery, direct administration of a drug via the intrathecal route into the subarachnoid space can help bypass the BBB and reach the cerebrospinal fluid (CSF). Although this is particularly useful for spinal anesthesia, chemotherapy, or pain management, it could not be used to deliver small, lipid-soluble drugs to the brain; however, the intrathecal route has since emerged as a useful and, in some cases, the ideal, route of administration for specific therapeutic protein and targeted disease combinations. siRNA duplexes are introduced by cationic lipid-mediated transfection, electroporation, or microinjection, and the intracellular expression of siRNAs from plasmid DNA by such routes. Delivery of siRNA lipid NPs (LNPs) via the intracerebroventricular (ICV) route demonstrated knockdown of target genes either in discrete regions around the injection site or in more widespread areas following ICV injection, with no apparent toxicity of, or immune reactions to, the LNPs.7 Here, we provide an overview of current advances in nanotechnology-based targeted therapy for the treatment of NDs.

Section snippets

Overview of neurodegenerative diseases

AD, PD, Huntington’s disease (HD), and ALS affect millions of patients worldwide.7., 8. AD is an age-linked progressive ND characterized by amnesia, diminished daily functions, and behavioral changes. The deposition of extraneuronal β-amyloid (Aβ) plaques and intraneuronal phosphorylated tau protein (neurofibrillary tangles) in vulnerable brain regions are the main factors involved in the pathological progression of AD.9 PD is another common disorder associated with a reduction in dopaminergic

Mechanism of nanoparticle uptake via the blood–brain barrier

The brain requires significant levels of nutrients to meet its energy demands. These cross the BBB via various routes, such as the absorption of endogenous (glucose and amino acids) and exogenous molecules, such as siRNA (exogenous double-stranded RNA that is taken up by cells, or enters via vectors, such as viruses) and miRNA, which is single-stranded and comes from endogenous noncoding RNA within the introns of larger RNA molecules.12 Small lipophilic molecules can enter the brain via passive

Role of siRNA for the treatment of neurodegenerative disorders

NDs evolve over time because of the progressive dysfunction of the central and peripheral nervous systems. Given that mutant alleles are responsible for several NDs, siRNA-based drug delivery might be an appropriate treatment option for NDs.24

Advantages of siRNA and nanocarrier systems for the treatment of neurodegenerative disorders

Double-stranded siRNAs have become widely used for silencing gene expression. When a duplex RNA enters a cell, it binds the protein machinery of the RNA-induced silencing complex (RISC). Synthetic RNAs used for gene silencing are usually 19–22 bp duplexes and can lead to high levels of translational suppression and reduction in the target protein. This length is sufficient to form a stable duplex and be recognized by the RISC and offers prolonged effects in terms of gene suppression; thus,

Disadvantages associated with the delivery of naked siRNA for the treatment of neurodegenerative disorders

The approaches used to deliver siRNAs to the CNS include the use of hydrodynamic injections, conjugation of the siRNA to a lipid or peptide, and fabrication of NPs. These carriers are usually administered via the intravenous (IV), ICV, or intranasal (IN) routes. The circulatory system poses the first barrier to siRNA once it has been administered systemically. Naked siRNA is more susceptible to destruction by nucleases and, thus, might be degraded quickly by RNase in the bloodstream. Chemical

Nanocarriers for the treatment of neurodegenerative disorders

Various NCs have been developed that can protect the siRNA from fast enzymatic degradation, offering diminished immunogenicity, increased blood retention time, and target-specific siRNA-based drug delivery. Commonly used nanocarriers for siRNA delivery include organic nanocarriers (ONCs), such as dendrimers, polymeric NPs, metallic NPs (inorganic NPs; e.g., magnetic NPs, AuNPs, silver NPs, and mesoporous silica NPs), nanomicelles, liposomes, and carbon-based nanomaterials, such as QDs and CNTs (

Concluding remarks

Although proving the clinical relevance of siRNAs against various NDs remains a challenge, nanotechnologies have demonstrated the potential to modify the physicochemical and biopharmaceutical properties of siRNAs to overcome the limitations associated with their systemic delivery and therapeutic effects against various NDs. Site specificity is the most significant challenge associated with siRNA that affects its efficiency against NDs and causes damage to other tissues. Liposomes, NPs,

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

We acknowledge the administration of Amity University Madhya Pradesh for providing support to write this article.

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