Articles
This article was written in collaboration with Dr. Dominik Witzigmann, Dr. Jayesh Kulkarni, and Dr. Atul Rangadurai, experts in RNA delivery and nanomedicine platform design.
For 67 years since its inception, the study of nucleic acids has captivated scientists, and yet, the core concept remains surprisingly elusive.
Let’s first take a quick stroll through the highlights of nucleic acid research over the past years, using Nobel Prizes as our guide:
Figure 1 – Nobel Prize Timeline in Nucleic Acids (1958-2025)
What exactly are nucleic acids?
By using a straightforward parallel, we’ll make the answer crystal clear once and for all. So let’s dive in:
Nucleic acids are the fundamental molecules that store, transmit, and execute genetic instructions - acting as the blueprints and messengers of life. At the molecular level, the key ingredient of all nucleic acids is the nucleotide, a 3-part molecule made of a phosphate, a sugar (either ribose in RNA or deoxyribose in DNA), and a base (A, T/U, C, or G).
These nucleotides are strung together to form long strands - single-stranded (like RNA) or double-stranded (like the DNA helix), like beads on a string. When we talk about single strands, we use nucleotides (nt) as a unit. For double-stranded structures like DNA, we refer to base pairs (bp), because two nucleotides bond across the two strands, forming the famous A–T and C–G pairs
This foundation is essential to understanding the structure and therapeutic use of each RNA and DNA type we list in this article.
Imagine the cell as a high-tech kitchen, and at the center of it all is the DNA - the master cookbook, locked safely in a vault inside the nucleus. This cookbook contains every recipe life might ever need, written in a long language of nucleotides, organized into coding regions (exons), the lines that matter, and non-coding regions (introns), the filler that gets edited out. Exons are like the essential ingredients in a recipe, while introns are the scribbled side notes you skip before cooking.
To prepare a specific dish (a protein), a chef makes a temporary copy of the recipe: this is the mRNA (messenger RNA), the recipe card, pulled from DNA and carried out to the kitchen workspace, - the cytoplasm.
Here, the ribosome - the cooking station made of rRNA (ribosomal RNA) and proteins - reads the mRNA and assembles the dish.
tRNAs (transfer RNA) are the ingredient runners, bringing in the correct ingredients (amino acids) one by one to build the final recipe (protein).
But before any cooking can begin, the recipe card (mRNA) must be prepped from the cookbook (DNA). snRNAs (small nuclear RNA) are the editors, cutting out the side notes (introns) and splicing together the meaningful lines (exons) to ensure the instructions are clean and readable. snoRNAs (small nucleolar RNA), meanwhile, are the maintenance crew, making sure the ribosome’s rRNA tools are in top shape.
lncRNAs (long non-coding RNA) and lincRNAs (long intergenic noncoding RNA) are the kitchen managers - they don’t cook but oversee which recipes get used and when, as not all recipes should be cooked. Some are outdated, overused, or even dangerous.
circRNAs (circular RNA), circular and stable, are like everlasting notepads, soaking up disruptive elements or storing instructions for later.
Enter RNA interference (RNAi) - the cell’s quality control system. It doesn’t rewrite the master cookbook (DNA); it simply intercepts some instructions (mRNAs) before they're executed.
RNAi acts as the factory’s editor-in-chief, working with a few sharp assistants:
- miRNAs (microRNA) act like red markers, scribbling over parts of the recipe to suppress it - the message is still there, but less readable.
- while siRNAs (small interfering RNA) act as scissors, cutting it up completely.
- If a recipe (mRNA) needs to be blocked rather than destroyed, ASOs (antisense oligonucleotides - fully synthetic molecules, not naturally occurring) are like tape strips, covering up bad instructions.
RNAi is not just a mechanism. It’s a strategy to mute toxic noise without altering your genetic script. It's reversible, targeted, and powerful - ideal for diseases driven by overexpression of unwanted recipes (proteins) rather than mutation.
And when we really need to change the cookbook permanently, say to fix a genetic disorder caused by production of faulty dishes (proteins), DNA editing tools like base editors or prime editors are brought in. These are GPS tools, guiding molecular scissors like Cas9 using gRNAs or sgRNAs (single guide RNA) to exact locations in the DNA to rewrite, repair, or remove faulty recipe lines. These changes are long-lasting, often irreversible - perfect for curing inherited diseases like sickle cell disease or congenital enzyme defects.
On the other hand, saRNAs (self-amplifying RNA) are highlighters, boosting the expression of underused recipes - amplifying protein production without changing the cookbook itself.
So, in the molecular kitchen, DNA is the cookbook, mRNA is the working recipe, and the rest of the RNA world acts as a team of specialists fine-tuning what gets cooked, how, and when. Understanding who does what - who makes proteins, who regulates this process, who destroys - is essential to grasping modern RNA and DNA therapeutics, each designed for unique challenges.
Figure 2 – Cellular Molecular Kitchen
All RNA types are currently under preclinical/clinical investigation; however, siRNA, ASO, and mRNA have already received regulatory approval for certain therapies (e.g., Onpattro for siRNA, Spinraza for ASO, Comirnaty for mRNA).
Despite the recent surge in approvals —(Figure 3), mRNA vaccines are the product of years of research- overcoming one major challenge: getting fragile and inflammatory RNA safely into cells. Scientists learned to synthesize mRNA in the lab, clean it up to avoid immune over-reaction, and optimize its sequence for better stability and protein production. The real breakthrough came with lipid nanoparticles (LNPs), which protect mRNA from degradation and shuttle it into cells effectively. This mRNA-LNP combo became the backbone of COVID-19 vaccines and now drives new treatments across infections, cancer, and rare diseases. What was once a biologically unstable molecule is now a programmable tool for future medicine.
Figure 3 – Recent Approvals in Nucleic Acid Therapeutics
Why Delivery Matters More Than Ever?
Now that we’ve shortly reviewed each nucleic acid modality, let's dive into how to deliver them accurately, ensuring they reach their intended target while avoiding clearance (like by the liver, if not intentionally targeted spot).
Delivering nucleic acid therapies like siRNA, mRNA or DNA isn’t as straightforward as giving a typical small-molecule drug. These molecules face major challenges once inside the body: they can break down quickly in the blood, they’re too large and negatively charged to enter cells on their own efficiently, and they can even trigger immune reactions. DNA faces an additional key delivery challenge – in sharp contrast to RNA modalities, which are active in the cytoplasm, DNA needs to be delivered to the nucleus to be active.
To overcome this, scientists use two key strategies:
• Chemical modifications that make these molecules more stable and less recognizable to the immune system,
• Delivery systems, like lipid nanoparticles (e.g. conventional LNP or long-circulating LNPs), that protect them and help them reach (target) the right cells.
Let’s take a closer look at how these two approaches work and why they’re essential for making nucleic acid-based therapies a reality.
Let’s begin with chemical modifications - when are they applied, and what purpose do they serve?
Nucleotides in DNA and RNA can be chemically modified. Thus, synthetic and naturally occurring nucleic acids in fact, composed of a more complicated alphabet rather than the simple four building blocks mentioned earlier. Short RNAs such as ASOs, siRNAs, or gRNAs use chemical tweaks for increasing durability, precision and to lower immunogenicity. mRNAs are modified to stay invisible to the immune system while being readable by cells. mRNA is much larger and the size difference significantly affects how they're delivered into cells and the types of chemical modifications they require.
Why this matters:
- Bigger molecule = harder to shield from degradation
- Heavier and bulkier = harder to fit into delivery vehicles
- Requires stronger stability tweaks and special carriers (LNPs
Small nucleic acid chemical modifications
Phosphorothioate (PS) backbone
Swapping non-bridging oxygen for sulfur boosts stability, improves protein binding, prolongs circulation, enhances resistance to nucleases, and improves pharmacokinetics.
Ribose sugar modifications (like 2’-O changes) further stabilize the molecules, improve binding affinity and confer nuclease resistance.
GalNAc conjugation is a clinically validated, precise, and efficient platform for delivering therapeutic oligonucleotides to the liver.
mRNA modifications
Cap & Tail Engineering
Optimizing 5′ caps and poly(A) tails is essential for efficient translation and stability of mRNA. 5’ Caps added to mRNA promote recognition by ribosomes and shields it from degradation, while Poly(A) tail is a long chain of adenines at the mRNA’s tail end; it enhances stability, nuclear export, and translation efficiency.
Nucleoside Modifications
Replacing uridine with pseudouridine or N1‑methylpseudouridine in mRNA reduces immune activation and boosts protein output.
Sequence & Structural Optimization
Beyond chemistry, optimizing codon selection, GC content, UTRs, and secondary structures boosts ribosome engagement, mRNA stability, and translational output. Customizing UTRs or even introducing internal ribosome entry sites (IRES) can enhance expression or bypass the need for traditional cap/tail elements, respectively.
Figure 4 – Nucleic Acid Modifications
With these modifications in mind, let’s now examine how these engineered nucleic acids are delivered into the body.
What delivery systems are used up to now?
When it comes to delivery systems mostly used for nucleic acids, two platforms predominate:
- Conjugates: Small RNAs (such as siRNA or ASOs) can be conjugated to a targeting ligand (e.g., antibody or small-molecule ligand) that home to particular cell types and thus broaden the therapeutic window. While GalNAc is the most clinically advanced example for delivery to the liver, conjugate technologies are being explored for applications beyond the liver, including muscle, tumors, and the CNS.
- Lipid nanoparticles (LNP) are typically composed of ionizable cationic lipids, helper phospholipids, cholesterol, and polyethylene glycol (PEG)–lipids that self-assemble with siRNA or mRNA into ∼100 nm particles, protecting their cargo from degradation, promoting cellular uptake (by targets) and exploiting pH-triggered endosomal escape to release payloads into the cytosol, an approach that underlies both the FDA-approved siRNA drug patisiran (Onpattro) and the mRNA-based COVID-19 vaccines. In particular, engineering LNPs and their physicochemical characteristics can tweak their delivery to the liver, spleen or other extrahepatic tissues. For example, long-circulating LNPs (lcLNP™) overcome rapid liver clearance, enabling delivery to hard-to-reach tissues like bone marrow or tumors. These next-gen LNPs demonstrate how rational design enables targeting beyond the liver. Check why for example, particle size is important here.
Importantly, developing an effective nucleic acid therapy involves optimization of both the therapeutic payload and delivery carrier. For instance, optimizing RNA sequence elements (e.g., UTRs, GC content) can further refine cell/tissue specificity of expression and expression kinetics when paired with next-gen LNP formulations.
In our next article, we’ll explore LNPs more deeply.
Indications and administration routes
Nucleic acid drugs target everything from genetic disorders (e.g., Onpattro or gene editing therapeutics for transthyretin amyloidosis), neurodegeneration (nusinersen for spinal muscular atrophy), and hypercholesterolemia (inclisiran or PCSK9 base editing therapeutics) to infectious diseases (mRNA COVID-19 vaccines) and cancer (personalized cancer vaccines or in vivo CAR-T). The mode of administration of nucleic acid drugs also varies depending on the application. For example, while nucleic acid-based vaccines are administered via injections into the muscle (intra-muscular, i.m.), therapies for cancer may be locally administered at the site of the tumor (intra-tumoral, i.t.). Other administration routes include intra-venous (i.v.) for LNPs and GalNAc–siRNAs to the liver and other tissues; sub-cutaneous (s.c.) for ASOs and some siRNA conjugates; intra-thecal for CNS-targeting ASOs and intravitreal for ocular nucleic acid therapeutics.
Hurdles & Next steps
Hurdles
Check the biggest challenges the field faces here.
Hopes
Targeting the genetic root cause: Unlike small-molecule or biologic drugs that act on proteins, nucleic acids can silence, express, replace or edit genes, offering the potential for long-lasting - or even curative - effects. Clinical validation: The recent approvals of antisense oligonucleotides, siRNA conjugates, and LNPs demonstrate that these platforms work in patients.
Expand delivery beyond the liver: Most approved drugs today exploit accumulation (tropism) at the liver; new ligands and particle designs are needed for targeting other tissues such as bone marrow, tumors, muscle, brain, lung, etc.
Gene editing & personalized mRNA therapeutics: Leveraging optimized LNPs are key to deliver CRISPR/Cas or base-editor cargoes for precise in vivo editing or for personalized mRNA vaccines encoding patients’ tumor neoantigens to fight their own cancers.
What regulatory trends are affecting nucleic acids?
The EMA’s new draft guideline (March 2025) lays out how mRNA vaccines must be built and tested - from defining the exact mRNA sequence (cap, UTRs, polyA tail) to controlling impurities like dsRNA (double stranded RNA) or RNA-lipid adducts that can affect translation or trigger immune responses. It clarifies that even upstream components like DNA templates and capping agents count as starting materials and must meet strict quality specifications. For finished products, nanoparticle size, encapsulation %, and in vitro functionality are now non-negotiables.
The Modality Breakdown: What’s Investable?
ASO - In mid-2024, Ionis Pharmaceuticals strengthened its ASO franchise by pricing a $500.3 million follow-on offering to advance its next-generation antisense candidates and commercial launches. That same year, Biogen and Ionis deepened their neuro-degeneration ASO pipeline via a 10-year, up-to-$1 billion strategic collaboration extension to co-develop novel antisense drugs for neurological diseases.
siRNA (GalNAc & LNP) – In April 2020, Alnylam Pharmaceuticals secured a landmark $2 billion strategic financing from Blackstone, providing non-dilutive capital tied to future royalty streams on inclisiran and reinforcing investor appetite for RNAi platforms. As of 2024, Alnylam’s first RNAi drug Onpattro (patisiran) achieved global revenues exceeding $500 million annually, highlighting the commercial viability of LNP-enabled siRNA delivery.
Infectious disease mRNA vaccines – On January 8, 2024, Moderna reported that its 2023 product sales reached approximately $6.7 billion - driven by $6.1 billion in COVID-19 vaccine revenues and $0.6 billion in deferred GAVI income - while its U.S. COVID-19 market share rose to 48 percent (up from 37 percent in 2022). The company reiterated guidance for roughly $4 billion in product sales in 2024 (primarily from COVID-19 and its forthcoming RSV vaccine), a return to organic sales growth in 2025, and a path to break-even profitability in 2026 through disciplined investment and new product launches
RNA-based cancer vaccines – RNA cancer vaccines are gaining momentum. In June 2025, BioNTech announced the acquisition of CureVac (valued at approximately $1.25 billion) to accelerate personalized oncology vaccines and leverage shared platform expertise. Clinical studies by BioNTech (e.g., BNT122 with Genentech) and Moderna (e.g., mRNA-4157 in combination with Keytruda) continue to advance in melanoma and other solid tumors, reinforcing investor confidence in this therapeutic modality.
In vivo gene editing - CRISPR Therapeutics ended 2024 with $1.9 billion in cash, supported by a $280 million offering and milestone payments from Vertex. Likewise, Intellia Therapeutics closed the year with $862 million, bolstered by a $650 million multi-tranche financing and strategic milestones. In September 2024, NanoVation Therapeutics and Novo Nordisk announced a multi-target partnership (up to approximately US$600 million) to develop in vivo base-editing therapies targeting cardiometabolic and rare diseases - highlighting interest in delivery platforms with extrahepatic targeting capabilities. In June 2025, Eli Lilly announced its $1.3B acquisition of Verve Therapeutics to advance one-time PCSK9 editing for cardiovascular disease
In vivo immunotherapy - An emerging area of investment is in vivo engineering of immune cells like CAR-T or myeloid therapies. In June 2025, AbbVie acquired Capstan Therapeutics and its targeted LNP platform for $2.1B to advance CPTX2309, a first-in-class in vivo anti-CD19 CAR-T program for autoimmune diseases. In May 2023, Myeloid Therapeutics raised $73 million to accelerate its mRNA-based immunotherapy pipeline including a first-in-class TROP2-targeting in vivo CAR-mRNA therapy delivered via LNPs. In September 2024, Me Therapeutics and NanoVation Therapeutics entered into a research collaboration to reprogram myeloid cells directly in the tumor microenvironment, with early preclinical data showing encouraging anti-tumor responses.
As more and more nucleic acid therapeutics move from bench to bedside, the future will be shaped not just by the payloads we design - but by how effectively we deliver them. Rationally engineered delivery platforms like lcLNP™ represent a key step toward that future.
Ready to dive deeper? If you haven’t yet begun with our foundational overview of nanomedicine basics, start here with our first article - then join us next as we unpack the science (and the art) behind LNP technologies: from the ionizable and helper lipids that give LNPs their biocompatibility and endosomal-escape power, to the PEG-lipid and cholesterol components that stabilize particle structure; we’ll walk you through cutting-edge formulation methods, dissect key characteristics (particle size, charge, encapsulation efficiency) and spotlight innovative strategies that are pushing delivery boundaries.
Download the PDF file here.
Written by
Dominik obtained his Ph.D. in Pharmaceutical Technology from the University of Basel in Switzerland. Following research projects at the University College London (toxicity), German Cancer Research Center (RNAi and cancer), University of Basel (targeted nanomedicines and DNA delivery) and the University of Zurich (mRNA-based genome editing), Dominik joined the team of Prof. Pieter Cullis at the University of British Columbia to focus on RNA delivery utilizing lipid nanoparticle (LNP) systems. Dominik had leadership roles within the NanoMedicines Innovation Network (NMIN - a Canadian Networks of Centres of Excellence), he co-founded and led NMIN`s NanoCore to support >30 projects with advanced nucleic acid delivery technologies, and he served as a Board Member of the Controlled Release Society Focus Group “Gene Delivery and Genome Editing”. Dominik has a proven track record in nanomedicines enabling tissue as well as cell specific drug and gene delivery. To translate next-generation LNP technologies into the clinic, Dr. Witzigmann co-founded and leads the LNP-nucleic acid company NanoVation Therapeutics
Dr. Kulkarni obtained his PhD from the University of British Columbia and has over 12 years of academic and industry experience in the nanoparticle drug delivery field. He has published over 40 peer-reviewed articles in prestigious journals and co-inventor on numerous patents. Dr. Kulkarni’s research has focused on the role of the various lipid components in LNP and the biophysics that governs particle formation. His work has contributed to clinical translation, including scale-up and manufacturing of LNP systems in accordance with GLP and GMP regulations. Dr. Kulkarni is a leader in the design and development of lipid nanoparticle (LNP) formulations of small molecule and nucleic acid therapeutics. He currently serves as the Chief Scientific Officer of NanoVation Therapeutics, an LNP-RNA formulation developer.
Dr. Rangadurai is a biochemist specializing in RNA biochemistry and structure. He holds a PhD in Biochemistry from Duke University and completed postdoctoral training at the University of Toronto and The Hospital for Sick Children. His research has focused on developing methods to study RNA and protein structure, as well as their interactions - expertise he now applies to advancing RNA-based therapeutics at NanoVation Therapeutics™.
Marija is a pharmacist with a PhD in Biopharmacy from the University of Geneva, and a cancer research (ISREC)–trained professional through EPFL, with over seven years of experience in nanomedicine. During her PhD, she worked on miRNA and STING ligand nanocomplexes for cancer immunotherapy, gaining deep expertise in nanoparticle characterization and translational workflows. Certified by the EU-NCL in nanobiotechnology and awarded by Innosuisse (Swiss Innovation Agency) with two prizes (jury and public) for the best life science project, she also earned support from FONGIT, Geneva’s leading deep-tech incubator. As the founder of NanoSphere and an active contributor to the Controlled Release Society (Communication Chair for the Gene Delivery and Editing Group (GDGE), and Industry representative at Nanomedicine and Nanoscale Delivery (NND)), Marija focuses on making next-gen medicine scientific advances more visible, understandable, and useful to the communities that can turn them into impact.