Beyond LNPs: 4 Non-Viral Delivery Vehicles Expanding The Possibilities Of mRNA Therapeutics
By Life Science Connect Editorial Staff
When it comes to non-viral delivery for mRNA therapeutics, lipid nanoparticles (LNPs) have emerged as the most promising vehicle thus far. Following the approval of Onpattro® and the mRNA-based COVID-19 vaccines, development of LNP-based mRNA therapeutics exploded.1 LNPs are appealing due to their ability to fully encapsulate RNA, prevent enzymatic degradation, and achieve high intracellular delivery.
However, LNPs also have limitations, including poor stability in vivo due to their relatively short half-lives; sensitivity to temperature, pH, contamination, and light; short blood circulation time; and toxicity and immune response concerns, including liver injury.2 To help broaden mRNA’s applicability across a wider array of indications, some nucleic acid therapeutics developers and platform companies are exploring innovative non-LNP, non-viral delivery vehicles. Explore the following insights about four of these exciting technologies, including how they work, as well as their strengths and obstacles, and how to overcome them.
1. Polymer-Based Delivery
How Does It Work?
Polymers are among the more high-profile non-viral delivery methods in the mRNA space. Though they have been around for as long as LNPs, no one previously had taken a systems approach to polymer-based discovery for non-viral delivery vehicles. Enter Nanite Bio, a company using high-throughput polymer discovery to build bespoke delivery vehicles. Nanite focuses on polyelectrolytes — a class of charged polymers that transport both DNA and RNA — and is developing degradable, bioreducible systems to enable a safer drug profile and redosability.
What Are The Advantages?
Polymers deliver both RNA and DNA, eliminating the need to use a split vector in gene insertion or editing, and enabling episomal expression of DNA. They achieve both durable and transient delivery, which is currently rare. They are also stable at room temperature, thus avoiding elaborate cold chain requirements.
What Are The Challenges?
From a regulatory perspective, LNPs have significant clinical precedent, creating a relatively streamlined pathway in comparison to polymers. However, the class of polymers used at Nanite Bio has been widely characterized within clinical applications, allowing the Nanite team to get ahead of the curve. To increase comfort and trust of polymer platforms, developers must demonstrate their ability to be regulatorily compliant via data packages, toxicology studies, and transitions from mice to primate studies.
2. Engineered Virus-Like Particles
How Does It Work?
In engineered virus-like particles (eVLPs), everything that makes viral particles infectious is removed and ribonucleoproteins (RNPs), RNA, or DNA are packaged for cell-type specific delivery. This approach gives the target cell transient exposure to the cutting nuclease, resulting in reduced off-target effects. Though nChroma Bio leverages LNPs in its lead program — a liver-directed epigenetic therapy to treat hepatitis B — their teams are using eVLPs for extrahepatic delivery of tissue-specific therapeutic molecules.
What Are The Advantages?
eVLPs are potent and stable. They are also modular and easily adapted to contain different components. eVLPs inherently avoid the liver and offer high levels of editing efficiency in targeted cells. There are strategies available to control the administered dose, which translates to a cost-of-goods advantage.
What Are The Challenges?
The primary challenge is the industry’s perception of cell-based manufacturing versus synthetic manufacturing. Though cell-based therapies are inherently more complex and more sensitive, there is also typically an overestimate of how much these drugs cost to make and a corresponding presumption that they will be inaccessible to patients given their anticipated price point. However, with the right approach and team, these problems are avoidable.
3. Cell-Specific Targeted Delivery Of RNA Payloads
How Does It Work?
Cell-specific targeted delivery of RNA payloads is done by understanding novel, cell-specific internalizing receptors, then identifying the best cell receptor for a given therapy and the ideal targeting ligand to engage that receptor for maximal uptake. Using this technology, Nosis Bio has demonstrated successful in vivo delivery to seven different tissues. This modality is very similar to N-acetylgalactosamine (GalNAc), which targets a receptor that is highly expressed on hepatocytes to ensure delivery to the liver. The difference is that these mechanisms target extra-hepatic tissues or can be added on to encapsulated delivery systems, i.e., LNPs or polymers, to include cell specificity.
What Are The Advantages?
With LNPs, biodistribution outside of the liver is limited and there are significant concerns around liver toxicity, redosability, and a lack of specificity. Furthermore, engineering a next-gen LNP requires empirical, combinatorial chemistry that makes it difficult to understand what’s driving biodistribution. As a result, translating the therapy from a petri dish to a rodent and then to a human is difficult and often unsuccessful.
However, when leveraging a receptor-based mechanism, researchers can study the human biology very closely, allowing teams to identify the right receptors (i.e., highly expressed, internalizing, and specific to a cell type) to achieve a predictable delivery profile. With the right system, treatment will be highly redosable, predictable, and viable long term.
In a recent success story, Verve, which was acquired by Lilly in July 2025, started by delivering a PCSK9 gene editor with a generic LNP. However, after facing pre-clinical toxicity concerns, they updated the molecule to decorate it with GalNAc to target the receptors on hepatocytes and improve the safety profile. This product is now being researched in clinical studies and generating promising data.
What Are The Challenges?
The biggest misconception with these delivery vehicles is that GalNAc and its asialoglycoprotein receptor (ASGPR) are the only system that can conduct effective receptor delivery. Though this system has been extraordinarily successful — seven FDA approvals and 100+ therapeutics in development3— it’s just the beginning for receptor-based mechanisms. With over 3,000 receptors in the human body, the question is how to efficiently identify the best receptor target for a given indication and cell type. Ideally, more biologists will become involved in the delivery of RNA to help build better target discovery and validation platforms.
4. Extracellular Vesicles
How Does It Work?
Extracellular vesicles (EVs) are small, nanometer-range particles that bleb off cells to carry cargo, such as nucleic acids and proteins, from the parent cells to other cells. In the product development space, these particles can be isolated from stem cells to evade the immune system and carry the regenerative-tissue and immune-modulating properties of stem cells to share signals that stimulate or reprogram cell function. At Aegle Therapeutics, teams are engineering EVs to be carriers of RNA that fuse with host cell membranes to deposit their cargo and initiate signaling cascades for regeneration.
What Are The Advantages?
EVs are quite distinct from LNPs and generally used for different applications. LNPs are ideal for delivering a specific RNA; however, if the intention is to deliver an array of cargo from a stem cell, EVs are a great choice. Thus far, EVs have proven effective for regenerative healing, including reducing the scarring from epidermolysis bullosa, a pediatric genetic disorder that manifests as blistering and erosion of the skin. Aegle has also used EVs to assist with accelerated healing and tissue regeneration in second-degree thermal burns.
.Tissue-specific targeting leverages the cell type specific to that tissue. For example, EVs from neuronal cells could be used to carry receptors across the blood/brain barrier to treat neurodegeneration from Parkinson’s disease or strokes.
What Are The Challenges?
Drug sponsors must identify ways to conduct GMP manufacture of EVs — which are derived from donor cells — in an efficient and reproducible way, including improving scale up into bioreactors for large-scale, systemic use. This challenge will likely require greater collaboration with CDMOs. There is also a misconception that EVs can perpetuate cancer due to a previous study that used EVs from animals with cancer. At Aegle, there is absolutely no use of EVs from donors with cancer, and there is no evidence to suggest that EVs from healthy donors cause cancer. More clinical data will help support the correction of this perception.
A World Of Potential
To maximize the impact and efficacy of mRNA therapies, it is vital to keep the innovation engine running. No RNA-delivery vehicle is one-size-fits-all: a diverse array of non-viral delivery vehicles is necessary for an expanded repertoire of mRNA therapies. With a wide range of delivery options, mRNA therapeutics will be poised to treat new indications and help new patient populations.
The content of this article originally appeared in an Advancing RNA live event. You can watch the full event here.
References
- Nele, V., Campani, V., Alia Moosavian, S., & De Rosa, G. (2024). Lipid nanoparticles for RNA delivery: Self-assembling vs driven-assembling strategies. Advanced Drug Delivery Reviews, 208, 115291. https://doi.org/10.1016/j.addr.2024.115291
- Tenchov, R., Bird, R., Curtze, A. E., & Zhou, Q. (2021). Lipid nanoparticles─from liposomes to mrna vaccine delivery, a landscape of research diversity and Advancement. ACS Nano, 15(11), 16982–17015. https://doi.org/10.1021/acsnano.1c04996
- Zhang, Y., Liu, H., Zhen, W., Jiang, T., & Cui, J. (2025). Advancement of drugs conjugated with GalNAc in the targeted delivery to hepatocytes based on Asialoglycoprotein receptor. Carbohydrate Research, 552, 109426. https://doi.org/10.1016/j.carres.2025.109426