Author: Simon Moe

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.

Detecting Neuroinflammation in Microglia and Astrocytes

Posted on by Simon Moe

The brain is one of the most complex and fascinating parts of biology. Thankfully, it’s also remarkably good at protecting itself. When exposed to a pathogen, an injury or even misfolded proteins, microglia and astrocytes function as the central nervous system’s (CNS) primary immune defenders. They mount an inflammatory response by releasing cytokines and working to contain the damage. Yet this same system can malfunction or not resolve, which manifests as devastating consequences.

Chronic neuroinflammation is now recognized as a shared characteristic across some of the most common and difficult-to-treat neurological conditions. A 2023 review in Signal Transduction and Targeted Therapy highlighted the dualistic nature of neuroinflammation: while acute responses serve a protective role, chronic or dysregulated inflammatory signaling can initiate and accelerate neurodegeneration, identifying these pathways as priority targets for therapeutic intervention (Zhang et al., 2023). A 2025 review in Science reinforced this view, noting that within Multiple Sclerosis, disease-modifying therapies targeting neuroinflammation have seen the most clinical success (Shi & Yong, 2025). This could suggest applications within neurological conditions where the same inflammatory mechanisms are at work.

Understanding how and where these inflammatory signals originate in the CNS is an active area of preclinical research. One cytokine being actively studied is IL-6. IL-6 is produced by several cell types, including astrocytes and microglia in the CNS. As a key mediator of inflammatory responses, it mediates pro-inflammatory effects through its trans-signaling, which occurs via soluble IL-6 receptors. Dysregulation of this mechanism may contribute to the chronic neuroinflammation seen in several neurological conditions. Characterizing how and when IL-6 is secreted from CNS cells is an important step toward understanding the neuroinflammatory processes underlying these disorders.

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Your Media Choice Might Be Designing Your T-Cell Fate

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Why Metabolism Matters in T-Cell Expansion

Adoptive T-cell therapies rely on generating metabolically fit, functional cells during ex vivo expansion—but this process often pushes T cells toward highly glycolytic, terminally differentiated states that limit their persistence and therapeutic potential. These metabolic programs begin shifting within hours of activation, therefore understanding early metabolic remodeling is essential for designing culture conditions that support durable, cytotoxic, and memory-enriched T-cell populations.

Researchers at Promega set out to address this challenge by systematically mapping how media composition and activation strength shape T-cell metabolism during the first 72 hours after stimulation. Using a suite of bioluminescent assays, they profiled intracellular energy cofactors, redox balance, and extracellular metabolites across several conditions. This approach revealed distinct, media-driven metabolic states that not only emerged early but also predicted downstream expansion, proliferation, and cytotoxic function.

Their work demonstrates how integrating metabolic profiling into in vitro expansion workflows can provide a more informed framework for optimizing T-cell manufacturing strategies.

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Insights from 3D Liver Models: Rethinking Fatty Liver Disease with Hormone Correction

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Liver disease is a global health challenge, affecting millions each year. The liver has a remarkable ability to regenerate; however, chronic damage arising from obesity, alcohol, or metabolic dysfunction can lead to irreversible failure. At the University of Edinburgh’s Centre for Regenerative Medicine, Professor David Hay’s lab is developing innovative ways to study liver function and disease using a lab-grown mini-organ. In this blog, we highlight how Dr. Hay’s lab is redefining liver disease research through 3D models that reveal how hormones influence metabolic health.

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Top 5 Luciferase Reporter Vectors You Didn’t Know You Needed (But Now Can’t Live Without) 

Posted on by Simon Moe

Ever spent your Friday night troubleshooting a cloning reaction that just won’t work? 

We’ve been there. So have thousands of other scientists. That’s why Promega and Addgene teamed up to create something game-changing: a curated collection of 600+ luciferase reporter vectors, designed to help you skip the cloning and get straight to the data. 

Addgene, the nonprofit plasmid-sharing platform trusted by researchers worldwide, and Promega, a global leader in luminescent assay technologies, have joined forces to make your gene expression, pathway analysis, and cell signaling experiments faster, easier, and reproducible. 

In this post, we’re spotlighting 5 standout vectors from the new collection that are making life in the lab a whole lot better. 

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Non-Pharmacological Approaches to ADHD: Exploring Inflammation and Omega-3s

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Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder that affects millions worldwide. Current therapeutic treatment relies on pharmaceutical approaches, but emerging research suggests that dietary supplements, such as omega-3 fatty acids, may offer complementary therapeutic options. A recent study published in the Journal of Psychiatric Research explores the relationship between inflammation and dietary supplements to determine how they might influence ADHD pathology. This work was conducted in Dr. Edna Grünblatt’s lab at the University of Zurich and was supported through Promega’s Academic Access Program. I had the chance to interview Dr. Natalie Walter, the lead author, to learn more about how her work offers potential opportunities for non-pharmacological interventions.

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Mapping the Mind: In Vivo Imaging of Synaptic Plasticity with HaloTag® Ligands

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The brain is constantly rewiring itself, fine-tuning connections that shape how we think, learn, and remember. But capturing those fleeting molecular changes as they happen — at the level of individual synapses and across entire brain regions — has long been a challenge in neuroscience. Now, thanks to recent advances in HaloTag® dye technology, researchers can visualize protein dynamics in living brains with stunning clarity and specificity.

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Alzheimer Disease and Metabolic Dysfunction: A Critical Intersection in Brain Health

Posted on by Simon Moe

This guest blog post is written by Alden Little, a Marketing Intern at Promega.

Alzheimer disease (AD) is one of the most devastating neurodegenerative disorders, affecting millions worldwide. While much attention has been given to amyloid plaques and tau tangles, emerging research suggests that metabolic dysfunction in the brain plays a crucial role in the disease’s progression. A recent study published in Acta Neuropathologica by Schröder et al. sheds new light on how astrocytes—the brain’s metabolic support cells—are affected in AD, and how their dysfunction impacts neurons.

Auguste Deter, a patient of Dr. Alzheimer, who first described the hallmark plaques and tangles of AD.
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Glo-ing Above and Beyond: Simplifying Science with MyGlo Reagent Reader

Posted on by Simon Moe

Introduction

When it comes to laboratory tools, few things resonate more than the experiences of researchers who rely on them daily. At the University of Cincinnati the MyGlo Reagent Reader has quickly become an indispensable lab companion, due to its compact design, affordability, and intuitive interface with tailored apps for Promega assays. But what truly sets the MyGlo Reagent Reader apart is how it empowers scientists to focus on their research.

Take Ipsita Kundu, a third-year PhD student at the University of Cincinnati working in Dr. Tim Phoenix’s lab. The Phoenix lab, dedicated to studying innovative brain tumor therapies, faced challenges with their outdated luminescence reader. They needed an affordable, reliable solution to streamline Ipsita’s experiments without compromising accuracy or efficiency.

The MyGlo Reagent reader is Nominated for a 2025 Select Science, Scientists’ Choice Award in the category of Life Sciences Product of the Year. Do you agree that it is a game changer? Vote today!

The MyGlo Reagent Reader was the answer. This blog highlights how this integrated solution is redefining laboratory workflows, enabling researchers to maximize productivity and maintain focus on groundbreaking discoveries. Let’s delve into Ipsita’s story and explore how MyGlo transformed her research.

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The Greatness of Glycogen: A Central Storage Molecule in Energy Metabolism

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Introduction

Glycogen is a fundamental molecule in energy metabolism, serving as the critical storage form of glucose that supports cellular health and energy homeostasis. As a polysaccharide, glycogen is essential for maintaining stable energy levels, particularly during periods of fasting and physical exertion. This article will examine glycogen’s synthesis, storage, and utilization, along with its broader significance in human health and disease. Understanding glycogen’s role can provide valuable insight into energy regulation and metabolic health.

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