Gene therapy has emerged as a transformative approach for treating various genetic disorders, cancer, and rare diseases, offering the potential for targeted, long-lasting solutions. As the field advances, the development of safe and efficient delivery systems is crucial to unlocking the full potential of these therapies. One of the most promising technologies in this area is the use of lipid nanoparticles (LNPs), which have proven to be highly effective vehicles for delivering nucleic acids, including mRNA, siRNA, and CRISPR cargo. Below, we explore the latest trends in gene therapy from an LNP perspective.
Expanding Role of LNPs in Gene Delivery
Traditionally used in mRNA vaccines, LNPs have gained prominence in gene therapy due to their ability to protect and efficiently deliver genetic material to targeted cells. Their success in COVID-19 vaccines has spurred renewed interest in leveraging LNP technology to deliver a broader range of therapeutic agents, including gene-editing tools like CRISPR-Cas9 and Base and/or Prime Editing therapeutics.
LNPs are appealing due to their biocompatibility, ability to encapsulate various types of nucleic acids, and the ease with which they can be chemically modified to target specific tissues. As a result, researchers are increasingly optimizing LNP formulations to address different therapeutic needs, paving the way for more targeted gene therapies with enhanced delivery efficiency and reduced side effects.
Targeted Delivery and Precision Medicine
Figure 1. Example of several types of popular targeting ligands: antibody, peptide fragments, and small molecules.
One of the most exciting trends in gene therapy is the growing ability to precisely target treatments to specific cells or tissues, reducing off-target effects and improving therapeutic outcomes. LNPs are at the forefront of this effort, with innovations in targeting ligands, antibodies, and aptamers being explored to enhance specificity.
By functionalizing the surface of LNPs with ligands that bind to specific receptors on target cells, researchers can achieve more localized delivery of gene therapies. This targeted approach not only boosts efficacy but also reduces the risk of unintended effects on healthy tissues, making it a crucial development for the future of precision medicine.
University of Pennsylvania: Pioneering work by researchers at UPenn has led to the development of LNPs designed to deliver RNA directly to fibroblasts in the liver. In the 2023 study published in Nature Communications, they demonstrated the use of novel LNPs tethered to a small molecule targeting ligand. These LNPs were used to deliver siRNA or reporter mRNA. This targeted approach had a 2-fold increase in silencing efficiency as compared to DLin-MC3-DMA-based LNPs, showing great promise for future applications in precision gene therapies for liver diseases.
Beam Therapeutics is attempting to develop targeted LNPs capable of delivering base-editing tools specifically to hematopoietic stem cells (HSCs) to treat sickle cell disease. These HSCs reside in the bone marrow and give rise to all blood cells, so delivering gene-editing components directly to these cells can effectively correct the mutation responsible for sickle cell disease. Beam’s work underscores how targeted delivery is critical for therapies that require precise cell targeting to achieve lasting therapeutic effects.
AstraZeneca is actively exploring antibody-functionalized LNPs in their early-stage gene therapy programs for immune-related diseases, aiming to deliver gene therapies with unprecedented precision to immune cells.
Overcoming Biological Barriers
One of the ongoing challenges in gene therapy is delivering genetic material across biological barriers such as cell membranes, blood-brain barriers, and immune defenses. LNPs are being engineered to overcome these barriers, enabling more precise delivery of therapies to difficult-to-reach areas like the central nervous system (CNS) and tumor microenvironments.
Recent advancements focus on fine-tuning LNP composition and surface chemistry to improve cellular uptake, enhance endosomal escape, and avoid immune recognition. As gene therapies expand into more complex conditions, such as neurodegenerative diseases and solid tumors, LNPs are being designed to ensure that the therapeutic material reaches its intended destination.
Reducing Immunogenicity
While LNPs have proven highly effective in delivering genetic payloads, reducing their potential to trigger immune responses is a critical focus area. Immune reactions can reduce the efficacy of gene therapies and lead to adverse side effects. Therefore, researchers are developing novel LNP formulations that minimize immunogenicity through the use of alternative lipid components or by modifying the surface of nanoparticles.
Some strategies include the de-PEGylation (removing polyethylene glycol from established and novel LNP formulations) and incorporating biodegradable lipids/polymers, such as polysarcosine, to reduce immune system recognition and reaction. These innovations are helping make LNP-based gene therapies safer for patients, particularly in chronic or repeat dosing scenarios.
Sustainability and Next-Generation LNP Manufacturing
Looking ahead, the next wave of LNP development will focus on enhancing sustainability and biodegradability. Researchers are exploring ways to create environmentally friendly and less toxic LNPs by using naturally occurring lipids or developing fully synthetic, biodegradable alternatives. These innovations could further reduce the potential for adverse reactions and make gene therapies safer for widespread use.
Moreover, as new gene-editing technologies such as base editors and prime editors emerge, LNPs will need to evolve to accommodate these more sophisticated payloads. Next-generation LNPs will be optimized for delivering larger, more complex gene-editing tools with high precision, opening up possibilities for tackling previously untreatable genetic conditions.
At Helix Biotech, we specialize in the development and manufacturing of lipid nanoparticle (LNP) systems tailored for gene therapy applications. Our state-of-the-art Nova™ LNP manufacturing equipment, helps enable and streamline the functionalization of the LNP surface. The modular nature of the platform allows for the addition of extra mixing modules and fluid streams for enhanced capabilities, e.g. layer-by-layer approaches and conjugation steps.
Ask us about how we can help with your LNP formulation, development, and manufacturing!