Can Nucleic Acid Therapeutics Disrupt the Market by Overcoming Drug Delivery Hurdles

BIS Research
7 min readMay 15, 2023

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Nucleic Acid Therapeutics
Nucleic Acid Therapeutics

In recent years, nucleic acid therapeutics have gained popularity in the field of precision medicine for their potential to treat a wide range of diseases, including genetic disorders, cancers, and infectious diseases.

Nucleic acid-based drugs, such as RNA interference (RNAi) and antisense oligonucleotides (ASOs), can target specific genes and inhibit or enhance their expression. This specificity has allowed for treatments that can be tailored to an individual’s genetic makeup.

However, the successful delivery of these nucleic acid-based drugs to target body cells has been a significant challenge in the development of these targeted therapies. This is because traditional drug delivery methods, such as intravenous injection or oral administration, are ineffective for delivering nucleic acids, as they are easily degraded by enzymes and cannot penetrate cell membranes.

Moreover, the delicate and complex nature of these molecules poses significant challenges to their manufacturing, handling, shipping, and long-term storage.

To address these major challenges which pose hurdles to the progress of the biopharmaceutical industry, novel drug delivery systems (DDSs) have emerged that can stabilize nucleic acids to provide a high-quality, accurate, and safe profile for therapies.

This article explores the challenges and opportunities for achieving stable formulations of nucleic acid therapeutics with novel DDSs.

Current Scenario and the Challenges

Over the past decade, the impact of NA-based biopharmaceuticals has been facilitated by breakthroughs associated with high-end manufacturing and pharmaceutical drug delivery.

As active pharmaceutical ingredients (APIs), NAs are complex and delicate molecules that require sophisticated processes during manufacturing, handling, shipping, and long-term storage to preserve their stability. This specialized handling results in the drugs being more expensive.

The criticality in manufacturing involves precise chemical synthesis that can be reproduced consistently across multiple batches while ensuring the integrity of the final product.

Another challenge is the successful delivery of NA therapeutics inside cells, which is necessary for the desired therapeutic effects. The delivery of NA therapeutics is complex due to their hydrophilic nature, large molecular size, and rapid degradation by nucleases.

Moreover, the negative charge of NAs makes them unable to penetrate the cell membrane, which limits their therapeutic efficacy. Therefore, advanced DDS is needed to protect the NAs from degradation and facilitate their delivery inside cells.

Various DDS have been developed, which include:

Liposomes: Liposomes are spherical vesicles composed of a phospholipid bilayer that can encapsulate hydrophilic and hydrophobic molecules. Liposomes are biodegradable, biocompatible, and non-toxic, making them attractive for drug delivery. However, their stability and drug loading capacity is limited, and their biodistribution and cellular uptake can be affected by various factors such as size, surface charge, and targeting ligands.

Polymers: Polymers such as polyethylene glycol (PEG) and poly (lactic-co-glycolic acid) (PLGA) have been used as DDSs for NA therapeutics. PEGylation of NA therapeutics can increase their circulation time, reduce immunogenicity, and improve their pharmacokinetics. However, PEGylation can also reduce the cellular uptake and gene silencing activity of the NA therapeutics. PLGA nanoparticles can encapsulate NA therapeutics, protect them from degradation, and improve their cellular uptake. However, their small size limits their drug-loading capacity.

Nanoparticle-based Drug Formulations: These are a promising option for drug delivery with numerous beneficial attributes, such as the size of the nanoparticle can be tuned to optimize cellular uptake, while the surface can be modified to promote targeting and binding to specific cells or tissues. Furthermore, nanoparticle formulations can protect NAs from enzymatic degradation and enhance the stability and integrity of the drug consistently.

The Opportunities

1. Use of Lipid Nanoparticles for Producing Protein Therapeutics inside Cells

The production of protein therapeutics inside cells is a promising approach for the treatment of various diseases, including cancer and genetic disorders.

However, delivering the nucleotide-based therapies required for such products into the cells can be a significant challenge, as up to 80% of the targets are located inside the cells.

Lipid nanoparticles (LNPs) are being investigated as a novel and innovative vehicle for the intracellular delivery of nucleotide-based therapeutics for the production of protein therapeutics in cells.

These nanoparticles are composed of a lipid bilayer that surrounds the therapeutic nucleotide, providing a protective and stable environment for the molecule to reach its target inside the cell. LNPs initiate cellular protein production after intravenous, subcutaneous, and pulmonary administration.

Moreover, the use of mRNA-based therapeutics has the potential to rectify the malfunctioning of a deficient or absent protein in diseased cells or induce new cellular functions that modify the pathological condition.

For instance, AstraZeneca’s advanced drug delivery teams are currently working on enhancing the efficacy and safety profile of the LNP-based drug delivery system. Collaborating with teams of the Chalmers University of Technology, they have used surface-sensitive fluorescence microscopy to analyze single ionizable lipid-containing LNPs one at a time as they interacted with a synthetic membrane that mimicked the endosomal membrane environment.

Furthermore, this new technique provides a deeper understanding of how protein accumulation on the surface of the LNPs, called a protein corona, influences the way LNPs interact with endosomal membranes leading to better penetration of drugs at targeted locations.

Increasing incidences of chronic genetic diseases are driving demand for such nucleic acid therapies, which is expected to disrupt the market through a rise in production and NA therapeutics manufacturing units.

According to data insights from BIS Research, the global nucleic acid therapeutics CDMO market was valued at $3.88 billion in 2022 and is expected to reach $14.19 billion by 2033, growing at a CAGR of 12.55% during the forecast period 2023–2033.

Nucleic Acid Therapeutics CDMO Market

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2. Employing Controlled-release Formulations

Controlled-release formulations in NA therapeutics can improve patient treatments by extending the life of medicines inside the body, resulting in less frequent dosing and easier administration, especially when given by injection.

This can be achieved through the use of various methods, such as biodegradable polymeric particles, implants, silica particles, and atomic layer deposition (ALD) of metal oxides.

Biodegradable polymeric particles, such as poly lactic-co-glycolic acid (PLGA) and polycaprolactone, can be used to control the release of medicines based on the diffusion and degradation characteristics of the particles. This allows for less frequent administration and has shown promise in preclinical studies, such as using PGLA nanoparticles as carriers for anti-cancer drugs, which increased their anti-tumor activity and reduced their side effects.

Biodegradable implants work on a similar principle, slowly releasing their contents and degrading over time. They are larger than polymeric particles and are often injected under the skin.

Silica particle-based controlled release is an attractive option, particularly for biological molecules because the body tolerates natural silicon, which is widely found in tissues and fluids. By combining biologics with silica particles, it is possible to create particles with specific sizes and shapes to influence their delivery characteristics. In preclinical experiments, the controlled release of an antibody from silica particles for up to two months after a single injection has been demonstrated.

Atomic layer deposition (ALD) is a dry, metal oxide film deposition process that allows sustained release over long time periods following the formation of nanoshells on the surface of the particles. The nanoshells are produced directly on particles of an active ingredient and have demonstrated potential in controlling drug release in preclinical development.

3. Developing Oral Formulations for Biologics

Pharmaceutical scientists have long sought to develop oral formulations for biologics as they offer a more convenient and patient-friendly alternative to injections. This can now be achieved through the novel DDS.

With the use of transient permeation enhancers (TPEs), the stability of NA-based therapeutics can be achieved. TPEs are excipients co-formulated with drug modalities to facilitate transport across the gastrointestinal tract.

TPEs work by increasing the fluidity of cell membranes or opening tight junctions, thereby allowing larger macromolecules such as peptides and antisense oligonucleotides to pass through.

Designing macromolecules that are better suited for oral delivery when co-formulated with TPEs can enhance stability against intestinal enzymes and increase half-life to account for variability in oral absorption.

4. Integration of Artificial Intelligence and Machine Learning

By analyzing extensive datasets from various sources, including clinical trials and molecular simulations, artificial intelligence (AI) and machine learning (ML) algorithms can identify novel strategies and materials for developing more effective DDSs.

Designing novel DDSs is a time-consuming and expensive process that involves selecting suitable materials, optimizing physicochemical properties, and characterizing the performance of the DDSs.

AI and ML can significantly accelerate this process by predicting the suitability of materials and optimizing the design of DDSs based on desired pharmacokinetic and pharmacodynamic properties.

Moreover, AI and ML can predict the stability, biodistribution, and efficacy of DDSs in vivo by analyzing their interactions with NA molecules and the biological environment.

Conclusion

The development of technology and the increasing understanding of the underlying molecular mechanisms involved in diseases are driving advances in the field of NA therapeutics.

The use of RNA-based therapeutics, such as mRNA and siRNA, for the treatment of cancer, genetic disorders, and infectious diseases is rapidly evolving.

However, the successful development of NA therapeutics depends on the ability to overcome drug delivery challenges associated with the complex and delicate nature of these molecules.

Novel drug delivery systems and the use of AI and ML have the potential to revolutionize drug delivery for NA therapeutics. The continued advancement of these technologies could lead to the development of more effective, targeted, and affordable treatments for a wide range of diseases.

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