LNP- and Bioconjugation-based Nonviral RNA Delivery Technologies to Gain Momentum in the Next 3 Years
RNA therapeutics is a rapidly expanding field of next-generation medicine. RNA therapy typically comprises 4 different classes of molecules: non-codingRNA (ncRNA), antisense oligonucleotide (ASO), messengerRNA (mRNA), and RNA aptamer.
Small ncRNAs are like a double-edged sword; they can either up- or down-regulate specific genes. Contrarily, long ncRNA can act as miRNA cushions, thereby indirectly affecting the gene expression. Both small and long ncRNAs have been shown to be essential in the treatment of cancer and infectious diseases. They could be easily designed for both druggable and non-druggable targets of small-molecule drugs. ASOs are typically single stranded and exhibit the characteristics of small ncRNAs. mRNA is being used as a vaccine candidate in the last two years, rather than drug molecules. RNA aptamers typically bind to protein molecules, thereby directly influencing their function.
Though RNA therapeutics offers several advantages, industry uptake of this technology has been low because the polyanionic molecules of RNA can quickly degrade, making delivery to a specific tissue or organ, absorption or endocytosis, and renal clearance major challenges. However, academic researchers and small- to mid-size companies have persisted in their efforts to develop stabilization and delivery technologies for RNA therapeutics. Current RNA delivery technologies are of two types: bioconjugation and lipid nanoparticles (LNPs). In bioconjugation, the RNA therapeutic molecule is anchored to a biological moiety, which could be carbohydrate, lipid, peptide, or antibodies. LNPs could be lipoplexes, liposomes, or exosomes. Although bioconjugation is mostly used for stabilization and delivery, LNP-based delivery has garnered the attention of many researchers and companies because of its ease of manufacturing and success of delivery. Other delivery technologies or methods, such as DNA nanostructures, spherical nucleic acids, and stimuli-responsive chemistry are in the early stage of development.
The success of RNA therapy requires a multidisciplinary (molecular biology, pharmacology, chemistry, and nanotechnology) approach. RNA therapeutics should be modified to improve pharmacological properties.
First, conventional LNPs could be modified with a charge opposite to that of the therapeutic and embedded with certain chemical moieties that will help in specific targeting. Second, nuclease protection could be achieved by RNA engineering to modify the nucleotide, sugar, or backbone. Third, conjugation with carbohydrate, lipid, antibody, or peptide would help with not only stabilizing but also targeting. Fourth, DNA origami, spherical nucleic acids, and stimuli-responsive nucleic acids offer ways to circumvent challenges.
The research is intended to answer the following questions:
- What are the driving factors for RNA delivery?
- What are the emerging delivery and stabilization technologies for RNA therapeutics?
- What challenges and impediments remain to the adoption of RNA therapeutics?
- What initiatives are industry participants undertaking to accelerate adoption?
- What are the specialized RNA delivery platforms that can achieve desired business outcomes, compared to naked RNA delivery?
Table of Contents
1.2 The Impact of the Top Three Strategic Imperatives on RNA delivery Technologies Industry
1.3 Growth Opportunities Fuel the Growth Pipeline Engine™
1.4 Research Methodology
2.2 Major Challenges Associated with RNA in Therapeutics
2.3 Delivery Challenges Associated with Targeting of RNA Therapeutics to the Site of Action
2.4 Research Context
2.5 Research Scope
2.6 Key Findings
3.2 Increasing Stabilization by Circularization of RNA
4.2 PEGylation, the Most Common Lipid Combination
4.3 Companies Developing Next-Generation Lipid Nanoparticles
4.4 Limitations of Using Lipid Nanoparticles
4.5 Reduced Toxicity in RNA Delivery
4.6 Companies Commercializing Exosome-based RNA Delivery
4.7 Companies Tapping into the Potential of Spherical Nucleic Acid-Based RNA Delivery
4.8 Companies Designing Platforms for Exosome Manufacturing
4.9 Polymeric Nanoparticles as Non-Viral Vectors
4.10 Polymeric Nanoparticle Subtypes with Promising Biocompatibilities and Low Toxicities
4.11 Companies Working on Polymeric Nanoparticles
4.12 Utilizing Peptides to Target Newer Hepatic Tissues
4.13 Subtypes of Peptide Nanoparticles Facilitating Advanced Delivery Functions
4.14 Emerging Participants in Peptide Nanoparticles Delivery
4.15 Spherical Nucleic Acids to Deliver to More Than 50 Cell Types
4.16 Use of Stimuli Responsive Nanotechnology as an Alternative Delivery Technology
5.2 Cholesterol Conjugation with siRNA for Delivery
5.3 Stakeholders Focusing on Improving Chol-siRNA Delivery
5.4 Vitamins and Other Lipids Being Researched for Conjugating siRNAs
5.5 Carbohydrate-siRNA Conjugates Lead the RNAi Delivery
5.6 Companies Focusing on GalNAc-siRNA Bioconjugation Platforms
5.7 Carbohydrate-siRNA Conjugates in Clinical Trials
5.8 Antibody-RNA Conjugates that Exhibit Long Half-life and Low Immunogenicity
5.9 Companies focusing on AOC Platforms that Improve Delivery Quality
5.10 Aptamer Conjugation for Improved siRNA Delivery
5.11 Stakeholders Developing Aptamer-Oligonucleotide Conjugates
5.12 Peptide-Conjugation-Increased Option for Ligand Selection
5.13 Stakeholders Utilizing Peptides to Target Newer Hepatic tissues
6.2 Exosome-Based Delivery, the Most Promising Delivery System
7.2 Patent Landscape
7.3 Key Investments and Companies to Watch
8.2 Growth Opportunity 2: RNA Circularization for Stabilization
8.3 Growth Opportunity 3: Conjugation of RNA with Antibodies for High Specificity
9.2 Technology Readiness Level (TRL)
10.2 Why Now?