Rethinking Lipid Nanoparticles

Why It’s Time for a Better Delivery Solution

Lipid nanoparticles (LNPs) have played a central role in the rise of RNA-based therapeutics and vaccines, including the rapid development of mRNA COVID-19 vaccines. But while LNPs have proven their utility in certain contexts, their limitations are becoming increasingly clear. As biologic therapies become more complex and personalised, we need delivery technologies that go further; safer, simpler, and more flexible.

LNPs and Their Challenges in Intracellular Delivery

LNPs are composed of ionisable lipids, cholesterol, and helper molecules that form nano-sized vesicles to encapsulate RNA or DNA for intracellular delivery. While effective at protecting cargo and enabling cellular uptake, LNPs come with significant trade-offs.

One of the most pressing issues is toxicity. The cationic or ionisable lipids used to form LNPs can trigger immune responses, inflammation, or cell death, especially when repeated dosing is required. This toxicity limits their use in chronic treatments, gene therapies, and cell-based applications where cell viability is critical.

Additionally, tissue targeting with LNPs is often poor or non-specific. Most LNPs naturally accumulate in the liver, which can be useful for some therapies but problematic for others that require precise delivery to tissues like muscle, lung, or brain.

Finally, manufacturing LNPs at scale is technically demanding, requiring microfluidics or high-shear mixing equipment, and strict cold-chain logistics. These constraints increase production costs and reduce global accessibility, particularly in low-resource settings or labs without specialised infrastructure.

Cold Chain Constraints and Stability Issues

Perhaps one of the most overlooked limitations of LNPs is their temperature sensitivity. LNP formulations typically require ultra-cold storage conditions, often -20°C or even -80°C, to maintain stability. This poses major challenges for distribution, storage, and day-to-day lab use.

Cold chain dependence is not only costly, but it also limits the flexibility and sustainability of LNP-based therapies. For researchers and developers working with live cells or running time-sensitive experiments, waiting for thawing or managing dry ice logistics becomes a real bottleneck. And in clinical or field settings, cold chain failure can mean lost product and disrupted care.

These stability issues hinder widespread adoption and make scalable biologic delivery more difficult, especially in decentralised manufacturing or global health contexts.

Limited Use in Primary Cells and Difficult Targets

Many LNP formulations perform well in established cell lines but struggle with primary cells, stem cells, or immune cells, which are often more sensitive and harder to transfect. The mechanical and chemical properties of LNPs can interfere with cell membrane integrity, reducing efficiency and viability in these harder-to-transfect systems.

In research settings, this means inconsistent results and limited utility across experimental models. In therapeutic applications, it raises concerns about safety, reproducibility, and regulatory approval, especially when working with engineered cell therapies or personalised medicines.

Introducing BubbleFect: A Smarter, Gentler Alternative to LNPs

Recognising these limitations, PartitionBio developed BubbleFect, a next-generation delivery platform inspired by liquid–liquid phase separation (LLPS). Unlike lipid nanoparticles, BubbleFect is a non-viral, non-lipid reagent that enables efficient intracellular delivery, without toxicity, complex equipment, or cold chain storage.

BubbleFect is room-temperature stable, easy to use, and gentle on cells. Just mix your biologic cargo with water, add the reagent, and apply it to cells. There’s no need for high-shear mixing or refrigeration, and results can be seen in as little as 4–24 hours.

In comparative studies, BubbleFect showed superior transfection efficiency, broader cell compatibility (including primary and hard-to-transfect cells), and significantly lower toxicity than leading LNPs. Whether you're working with mRNA, CRISPR components, or proteins, BubbleFect gives you a reliable, scalable alternative that fits into any lab or therapeutic workflow.

As the field of biologic delivery evolves, it’s time to move beyond the limitations of lipid nanoparticles. With BubbleFect, the future of intracellular delivery is simpler, safer, and ready to scale.