Beyond the Liver: How Liposomal LNPs Are Expanding the Reach of mRNA Delivery

Posted on by Simon Moe

Introduction

Lipid nanoparticles (LNPs) have transformed mRNA delivery. From COVID-19 vaccines to the first approved RNAi therapeutic, ONPATTRO (Patisiran), LNPs have proven their ability to ferry nucleic acid cargo into cells with speed and efficiency (Huang, 2019). Despite this transformation, most clinically deployed LNP formulations share a significant constraint: following intravenous administration, roughly 90% of the injected dose clears to the liver within an hour. If your target is a hepatocyte, that is hardly a hindrance. It’s a serious limitation if you need to reach the spleen, lymph nodes, pancreas or other extrahepatic tissues, all of which are organs of major interest in immunotherapy, vaccine development and metabolic disease research.

A new paper from Pieter Cullis’s laboratory at the University of British Columbia (UBC) offers a structural solution to that problem. Their design, termed a ‘liposomal LNP’, reengineers the architecture of the particle itself to achieve dramatically longer circulation lifetimes and improved transfection in tissues that standard formulations have largely missed.

What are Lipid Nanoparticles?

LNPs enable fast transfection of a wide variety of cells, facilitating the transport of mRNA, DNA and siRNA into cells to induce transient expression in a short period of time (mere hours for mRNA and one to two days for DNA). They are a powerful tool that rose to broad public awareness through their use in COVID-19 vaccines, which delivered spike protein mRNA as cargo. Beyond vaccines, LNPs have been applied therapeutically as the delivery vehicle for ONPATTRO, which treats polyneuropathy of hereditary transthyretin-mediated amyloidosis (Huang, 2019).

The most widely studied LNP formulation, such as the ONPATTRO-like composition, consists of four components: an ionizable lipid, a helper lipid, cholesterol and a PEG-lipid. At physiological pH, the ionizable lipid is neutral and resides in a hydrophobic oil-like core surrounded by a lipid monolayer. This structure is highly effective at transfecting hepatocytes, but its rapid hepatic clearance limits its utility for reaching other tissues.

A Structural Redesign: What Makes the Liposomal LNP Different

Standard ONPATTRO-like formulations have a lipid monolayer surrounding an oil droplet core. The UBC team’s publication reasoned that dramatically increasing the proportion of bilayer-forming lipids, specifically equimolar egg sphingomyelin (ESM) and cholesterol, could fundamentally change what the LNP looks like (Cheng, 2025).

The authors explored various bilayer-to-ionizable lipid molar ratios (RB/I) to see how they modified the structure of the particle. They found that an RB/I of 4 resulted in particles that transition to a true liposomal architecture consisting of a lipid bilayer enclosing an aqueous interior with a solid core suspended inside. Cryo-electron microscopy confirmed that approximately 84% of particles at this ratio adopt this bilayer structure, with the solid core occupying roughly 30% of the interior. LNP sizes across all tested ratios remained in the 40–60 nm range, confirming that the structural shift happens without meaningful changes in particle size.

Why the Structural Change in Liposomal LNP Affects Assembly and Delivery

The liposomal LNP exploits pH-driven structural transitions at both the assembly and delivery stages, explaining how a particle dominated by bilayer lipids can remain transfection-competent.

Assembly: When an ethanol-lipid mixture meets an acidic aqueous buffer (pH 4) containing mRNA, the positively charged ionizable lipid binds the negatively charged mRNA, forming a core complex. This complex acts as a nucleation point for the deposition of ESM/cholesterol bilayer lipid. As pH rises to 7.4 during formulation, ionizable lipids in the outer monolayer shift to a neutral form and migrate inward, expanding an oil droplet core. The mRNA dissociates from the oil core and resides in the aqueous interior where it is protected within the bilayer.

Delivery: After endocytosis, the acidic endosomal environment reverses this process. The ionizable lipids become positively charged again and migrate to the outer surface of the LNP, causing the solid mRNA-containing core to extrude outward from the liposomal bilayer. This positively charged protrusion interacts with the negatively charged endosomal membrane, triggering fusion and releasing the mRNA into the cytoplasm for translation. The authors describe this as a localized “warhead” mechanism—a structural consequence of the bilayer architecture, rather than a simple membrane-disruption event.

Exploring the Performance of the Liposomal LNP

The authors utilized NanoLuc® mRNA as a reporter payload throughout the study. From in vitro transfection efficiency to whole-animal imaging, it allowed the authors to detect differential expression that would have been difficult to detect with less sensitive reporters.

The performance of the Liposomal LNP tells a compelling story. In vitro, the RB/I = 4 formulation matched or exceeded the transfection potency of the ONPATTRO-like composition in Huh7 cells across a wide dose range, while also proving to be the most stable on the shelf. After 63 weeks at 4°C, it maintained greater than 80% mRNA encapsulation with less than 20% size increase, and produced the highest mRNA integrity and translatability of any tested ratio.

SPECT/CT imaging of whole animals with the Liposomal LNP showed a circulation half-life approximately 15-fold longer than the standard ONPATTRO-like formulation, a direct consequence of the bilayer exterior adsorbing roughly half the plasma protein load. This reduced exterior plasma protein load means less macrophage recognition, less clearance and more time in circulation to reach tissues beyond the liver. That improved lifetime in circulation translated into improved tissue access. Ex vivo organ analysis showed 50-fold greater luminescence in the spleen and 150-fold greater in the inguinal lymph node compared to the standard formulation. Meaningful signal was also detected in the pancreas, a tissue rarely reached through conventional LNP formulations. Immunofluorescence confirmed delivery was localized to macrophages at the marginal zone of the spleen and subcapsular sinus of the lymph node.

It is also worth noting that the liposomal morphology held up when tested with the ionizable lipids used in the BNT162b2 and the mRNA-1273 COVID vaccines, suggesting this is a generalizable design.

Expanding Use of NanoLuc® mRNA: UBC RNA and Formulation Core

Throughout this study, NanoLuc® mRNA served as the reporter payload. In vitro, NanoLuc® luminescence normalized to total protein provided a sensitive, linear measure of transfection efficiency across a wide dose range. In vivo, it enabled whole-animal IVIS imaging using the Nano-Glo® Fluorofurimazine substrate, with quantification extended to ex vivo organ homogenates using the Nano-Glo® Luciferase Assay System. NanoLuc® Luciferase sensitivity enabled detecting differential expression in tissues as small as inguinal lymph nodes and the pancreas. Detecting meaningful signal from a lymph node or pancreas can be challenging and thus successful detection demonstrates the exceptional performance of NanoLuc® Luciferase.

The authors synthesized their NanoLuc® mRNA in-house, a capability not universally available to research groups. We have partnered with the University of British Columbia RNA and Formulation Core to close that gap, enabling distribution of NanoLuc® mRNA across the core’s academic and industry network. Researchers who want to investigate LNP delivery, optimize formulations or validate mRNA constructs can now work with the RNA and Formulation Core to acquire NanoLuc® mRNA without the overhead of in-house synthesis. Work from UBC has contributed foundational understanding for LNP formulations, and now through their core they enable NanoLuc® mRNA development for any interested scientist.

Conclusion

The work from UBC demonstrates what becomes possible when mRNA delivery can reach beyond the liver, but the findings are only useful if researchers can access the tools to replicate and build on them. That’s where the UBC RNA and Formulation Core comes in. By partnering with Promega to distribute NanoLuc® mRNA, the Core gives researchers direct access to the same reporter used in this study, without the overhead of in-house synthesis. Whether you’re optimizing an LNP formulation, validating extrahepatic delivery or exploring mRNA constructs for a new application, you can now work with the Core to get started.

Interested in learning more about the UBC RNA and Formulation Core? Explore their website.

Learn more about the full NanoLuc® portfolio.

Citations

Cheng, M.H.Y. et al. (2025) Liposomal lipid nanoparticles for extrahepatic delivery of mRNA. Nature Communications 16, 4135.
Huang, Y.Y. (2019) Approval of the first-ever RNAi therapeutics and its technological development history. Prog. Biochem. Biophys. 46, 313–322.

The Filter You Didn’t Choose

Posted on by Elise Johnson

This is the second post in a series leading up to the 16th annual International Forum on Consciousness, taking place in Madison this May, hosted by the BTC Institute, Promega and Usona Institute. The Forum gathers scientists, philosophers, and practitioners from dozens of different fields to investigate the nature of the mind. This year’s theme, “Unspoken Intelligence,” explores forms of perception and knowing that fall outside conventional cognition.

When she thought about a dog, she saw a dog, more specifically, every dog she had ever encountered, cycling through her mind like a card catalog with pictures attached. She assumed everyone did this. When she discovered they didn’t, that most people access something more like an abstract concept hovering somewhere between language and image, she was genuinely surprised. Temple Grandin had always known her mind didn’t work the way people expected. What she didn’t know, until she was an adult, was the specific shape of the difference.

Most of us know this story, or one like it. We understand that some minds filter experience differently, but the science on this doesn’t stop where the conversation usually does.

For most of its history, the field that mapped minds like Grandin’s looked at those that didn’t fit the available systems and concluded the minds were broken. (It didn’t ask whether the systems were.) More recently, the conversation has been reframing those minds not as deficient but as different.

For many people, that reframing has been transformative, changing how educators teach, how clinicians diagnose, and how workplaces are designed. We are now more familiar with alternative cognitive profiles such as autistic pattern recognition (like that experienced by Grandin), ADHD-associated divergent thinking, and the hyper-focused depth of what researchers call monotropic attention. These are not broken versions of normal cognition. They are different architectures, each with genuine capabilities that other minds aren’t built to produce.

The terms most commonly used to describe these differences, neurotypical and neurdivergent, are useful shorthand but they describe a binary the underlying biology doesn’t support. Cognitive traits distribute across a population the way most biological traits do. “Neurotypical” minds are simply closer to the statistical center. What we call “neurodivergent” can be better understood as the part of that population that differs visibly enough from the statistical center to make the variation impossible to ignore.

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Piecing Together the Primate Gut Microbiome: Known Residents and Novel Species

Posted on by Anna Bennett

If you’ve read anything about the gut microbiome in the last decade, you’ve probably encountered a familiar setup: researchers collect stool samples, sequence the microbial DNA, and draw conclusions about gut health based on what microbes populate the gut. It’s a practical approach because stool is relatively easy to collect and doesn’t require invasive procedures. But how well does a stool sample represent the health of the entire intestinal tract?

A team of researchers at the Quadram Institute Bioscience and UK Health Security Agency set out to answer this question in primates1. They characterized the intestinal microbiome of cynomolgus macaques, a primate commonly used in biomedical research because of its genetic and physiological similarities to humans. Rather than relying on stool alone, the team collected samples from six distinct regions along the intestinal tract in 24 captive-bred animals ranging in age from 4 to 20 years.

Four hands putting jigsaw puzzle pieces with image of large intestine together.
Continue reading “Piecing Together the Primate Gut Microbiome: Known Residents and Novel Species”

The Body Already Knows

Posted on by Elise Johnson

This is the first post in a series leading up to the 16th annual International Forum on Consciousness, taking place in Madison this May, hosted by the BTC Institute, Promega and Usona Institute. The Forum gathers scientists, philosophers, and practitioners from dozens of different fields to investigate the nature of the mind. This year’s theme, “Unspoken Intelligence,” explores forms of perception and knowing that fall outside conventional cognition.

There’s a quote that travels well in some intellectual circles:

You don’t have a soul. You are a soul. You have a body.

There’s something genuinely relieving about that idea. It locates the real you somewhere above the fray, untouched by the body’s demands and indignities, the consciousness that thinks and persists while the body handles the inconvenient work of being hungry and tired and sick. The thinking part is what counts.

Plato thought something similar. So did Augustine. As did Descartes. Kant, too. The idea that the thinking self is separate from and superior to the body is Western civilization’s default setting.

It sounds like wisdom. It is also, I’ve come to think, exactly the wrong way to understand what we are.

Here’s a different text, one most millennials can recite from memory. In the opening verse of “Lose Yourself,” Eminem rattles off a visceral catalog of physical symptoms: sweaty palms, weak knees, heavy arms, vomiting. The body staging a complete revolt while the mind tries to execute a plan, until the moment on stage when the mouth opens and nothing comes out. The mind wanted to perform, but the body said no.

Nobody who has memorized those lyrics thinks of them as a description of embodied cognition. They file it under music, or nostalgia, or just a song they played too loud in a car they didn’t own. But the nervous system doesn’t care what you call it, because the body doesn’t catalogue in words.

This is the thing the soul-body quote gets wrong: the body isn’t a vehicle the self rides around in. It’s already thinking, already keeping score, already running a process the mind is only partially aware of. The question is what to do about that.

Continue reading “The Body Already Knows”

Stolen Chloroplasts and the Chrysalis of Complex Life 

Posted on by Elise Johnson

Despite its many mysteries, a chrysalis is one of the most familiar transformations in nature. We know what goes in. We know what comes out. For a long time, what happened in between was essentially invisible to us. Not because we weren’t curious, but because the mechanism was sealed inside something the size of a thumbnail, and we had no way in.

This same invisibility exists on a much older and much larger scale.

Sometime around two billion years ago, a cell swallowed a bacterium and, instead of digesting it, kept it alive inside itself. This process, called endosymbiosis, is arguably the single most consequential event in the history of complex life. The bacterium became a permanent resident, and over billions of years of co-evolution, it became something else entirely: the mitochondria that power every complex cell on earth. Without it, the living world as we know it doesn’t exist.

Scientists have known for decades that this kind of cellular acquisition had to have occurred. What has proved harder to explain is not that it happened, but how it started. What did the earliest molecular steps actually look like from the inside?

In the ocean, there is a microscopic single-celled organism called Rapaza viridis. It hunts algae by propelling itself through the water on whip-like appendages called flagella. That hunt may be showing us the beginning of a modern endosymbiosis: the same process that gave every complex cell its mitochondria and every plant its chloroplasts.

Continue reading “Stolen Chloroplasts and the Chrysalis of Complex Life “

New Study Suggests Cancer Research Has an Age Problem

Posted on by Kelly Grooms
White lab mouse among test tubes overlaid with a blue DNA helix.

Most cancer research relies on young, healthy mice. Most cancer patients are not young. Could this disconnect between model organism and patient, which ignores the impact of the physiological realities of aging, explain why some therapies perform well in the lab but not in clinical trials? Focusing on lung cancer, a study published in Nature investigated what happens when these two realities, young and old, finally meet in the lab (1). The answers could reshape how we think about cancer research and the impact of aging on metastasis and disease progression.

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ISO 14001 in Biotech: What It Means for Life Science Researchers

Posted on by Promega

This blog is guest-authored by Corey Meek, Corporate Responsibility Program Manager

Promega has achieved ISO 14001 certification for environmental management systems.

Over the past few years, we’ve noticed that our customers’ procurement teams are increasingly asking us about ISO 14001 certification. As a company that has long set ambitious sustainability goals, we have been heartened to see more labs and life science companies incorporating environmental impact into their planning and purchasing. To support our customers looking for external validation of environmental management, we announced in mid-2025 that Promega Madison has achieved ISO 14001:2015 certification.

ISO 14001 certification goes far beyond reporting and reducing our carbon footprint. It represents how we integrate environmental sustainability across complex operations to achieve ambitious environmental objectives. For scientists evaluating potential suppliers, it signals our commitment to sustainability without compromising the product consistency and reliability your lab depends on.

What is ISO 14001?

ISO 14001 is an internationally recognized standard that defines requirements for environmental management systems. This captures the processes we use to identify, control and reduce our environmental impacts. Unlike regulations that set specific pollution limits, ISO 14001 establishes a framework that includes setting environmental objectives, implementing operational controls, monitoring performance and driving continual improvement. The standard mandates leadership accountability and requires a third-party audit, annual surveillance and recertification every three years.

In practice, this means that we document every significant environmental aspect of our operations, from chemical waste streams in manufacturing to energy consumption in our facilities. We establish controls for each: procedures for handling hazardous materials, protocols for managing wastewater, systems for tracking energy use. We document incidents, investigate root causes, train employees and implement corrective actions to stay on target. Third-party auditors verify annually that these systems are functioning effectively and meeting the requirements of the ISO 14001 standard.

Our certification isn’t a one-time checkbox; it’s a commitment to continual improvement through the same management disciplines used in quality systems. We identify risks and establish operational controls for significant environmental aspects. When issues arise, we use structured nonconformance and corrective action processes.

How Does Environmental Management Connect to Quality and Supply Chain Reliability?

ISO 14001 and ISO 9001 (Quality Management Systems) share fundamental processes such as document control, training and competence requirements, change control procedures, nonconformance and corrective action (NC/CAPA) systems, equipment controls and internal audit protocols.

At Promega, all our major manufacturing and R&D sites are covered by both certifications. When we evaluate changes through our change control process, we assess both quality and environmental implications simultaneously. The partnership between our quality assurance and environmental management teams strengthens both systems and reduces operational blind spots.

This integration is important because environmental management doesn’t operate separately from product development and manufacturing. Hazardous materials handling, for example, requires environmental compliance, worker safety protocols and quality control simultaneously. The discipline required for ISO 14001 certification directly supports the manufacturing consistency researchers depend on for reproducible results. Environmental incident management and emergency response protocols reduce disruptions that could affect product availability and distribution.

What sustainability metrics are we measuring?

 ISO 14001 certification requires us to establish measurable environmental objectives and monitor our performance against them. Our organizational objectives include regulatory compliance verification, greenhouse gas emissions reduction, water consumption reduction and waste reduction. For example, we’re currently managing 87% of our hazardous waste through reclamation and recovery methods.

These objectives are monitored through multiple mechanisms: energy consumption and natural gas usage tracking, environmental incident documentation and analysis, internal and external compliance inspections, third-party assessment, and regular management review of performance data.

These quantifiable objectives are more powerful than aspirational statements. Annual third-party audits provide independent verification of our environmental performance. When procurement teams evaluate suppliers, they can choose to rely on ISO 14001 certification rather than conducting their own environmental audits. Most importantly, we approach sustainability strategically and responsibly by building robust processes rather than looking for quick wins. This means our gains are scalable, while safeguarding the consistency researchers using Promega products need for reproducible results.

ISO 14001 at Promega: Looking ahead

This certification requires us to demonstrate through third-party audits that our environmental management systems are effective over time. By focusing on measurable objectives and continuous improvement, we’re reducing our environmental impact in responsible ways that align with established standards and expectations.

In upcoming articles, we’ll explore how these ISO 14001 principles apply to processes and operations at Promega. Environmental management isn’t an isolated program; it’s infused in everything we do, from early product development to shipping of ready-to-use kits. As sustainability becomes increasingly important in procurement decisions, we’re committed to the environmental transparency and operational discipline that support your research goals.

Corey Meek is the Corporate Responsibility Program Manager at Promega.

Learn more about Promega Corporate Responsibility at https://www.promega.com/corporate-responsibility-csr/

Down the Rabbit Hole: The Search for New England’s Disappearing Cottontail

Posted on by Anna Bennett

Connecticut is a small yet ecologically interesting state. Over 85% of the human population lives in cities, yet more than 60% of the land is covered by forest, creating a diverse mix of habitats where wildlife and urban life overlap. In this landscape, bobcats have staged an impressive comeback over the past several decades, reclaiming their role as one of the region’s top predators. But as bobcat numbers rise, a quieter story is unfolding alongside them: the New England cottontail, the region’s only native rabbit, is vanishing.

a brown rabbit facing the camera with grass in the background.
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When Cancer Research Depends on Quality RNA: Maxwell® RSC in the Lab

Posted on by Promega

Reliable molecular research starts with reliable sample preparation. Two recently published cancer biology studies illustrate this well, and both studies relied on the Maxwell® RSC platform to extract RNA from formalin-fixed, paraffin-embedded (FFPE) tissue, the archival format that makes up the bulk of clinical pathology material.

With Maxwell Instruments and chemistries for FFPE samples, RNA quality is suitable for many critical assays.

Mapping Molecular Targets in a Rare Thyroid Cancer

A 2025 study published in Endocrine Pathology focused on poorly differentiated thyroid carcinoma (PDTC), a rare and aggressive thyroid cancer subtype with limited treatment options once surgery is no longer curative (1). The research question was straightforward but clinically urgent: how many PDTC cases harbor mutations that could be targeted with existing or emerging therapies?

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Before the First Dose

Posted on by Elise Johnson

Kierkegaard observed that one of humanity’s enduring tensions is that while life can only be understood backwards, it must be lived forwards. It’s a truth medicine knows intimately: in the treatment that worked until it didn’t, the resistance that arrived without warning, the moment a doctor has to tell a patient that the drug that was helping has stopped. Not because anyone made a mistake, but because the critical knowledge that would have mattered arrived too late, if at all.

A recent paper from the National Cancer Institute is, in a small but meaningful way, science’s pursuit of that elusive foresight: an understanding that emerges early enough, for once, to change what happens next.

The Elegant Idea

For decades, chemotherapy has worked by brute force, flooding the body with toxins designed to kill rapidly dividing cells. The problem is that rapid division isn’t unique to cancer. Hair follicle cells, gut lining cells and immune cells also divide rapidly, which is why patients lose hair, lose energy and become susceptible to infection. Chemotherapy targets a behavior, but the drug has no way to tell a healthy cell from a cancerous one.

Antibody-drug conjugates (ADCs) change that. Instead of targeting what cancer cells do, they target what cancer cells are. Cancer cells tend to display certain proteins on their surface in far greater numbers than healthy cells do. The antibody is engineered to seek out those proteins specifically. It navigates to its target, binds and waits for the cell to do what cells routinely do: pull it inside. Once there, the cell’s own digestive machinery (the lysosome) breaks down the chemical tether holding the toxin to the antibody, releasing the toxin to kill the cell from within. More than a dozen ADCs have received FDA approval in recent years, and the field is evolving fast.

What the Cell Does Next

But cancer cells don’t simply accept their fate. Even when an ADC delivers its payload perfectly—the antibody finds its target, the cell pulls it inside, the lysosome cuts the tether—a pump embedded in the cell membrane can grab the released toxin and throw it back out before it causes damage.

The delivery worked. The package got ejected anyway.

These pumps—ATP-binding cassette transporters, or more plainly, efflux pumps—are a normal feature of cell biology. Their job is cellular housekeeping, clearing out unwanted or toxic substances before they cause damage. Under the pressure of drug treatment, cancer cells do what life has always done under pressure: the ones best equipped to survive do. The same mechanism that has shaped living things for billions of years now works against the treatment. Not all cancer cells are identical, and the ones that happen to produce more pumps survive while others don’t, gradually shifting the tumor toward resistance.

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