Impact of Lipid Nanoparticle Structures on Cellular Uptake Efficiency

Scientists from RMIT University and Osaka University have made a significant breakthrough in understanding how the internal structure of lipid nanoparticles—specifically cubosomes—affects their ability to be absorbed by cells. Their study, published in the journal *Small* on June 16, 2025, reveals that certain shapes of lipid nanoparticles can enhance cellular uptake by as much as eight times compared to traditional liposomes. This advancement has important implications for the design of more effective drug and mRNA vaccine delivery systems.

Lipid nanoparticles are vital carriers for drug and gene delivery, particularly highlighted by the success of mRNA COVID-19 vaccines. However, a major hurdle in nanomedicine is the inefficient uptake of these nanoparticles by target cells. According to Sue Lyn Yap, the first author of the study and a Ph.D. candidate at RMIT University, "Most nanoparticles are taken up by cells through pathways that trap and degrade them, with studies indicating that less than 2% of gene therapies reach their intended target inside the cell."

The research focused on two types of lipid nanoparticles: liposomes, which have a simple layered structure, and cubosomes, which feature a complex 3D cubic architecture. The internal shape of these particles significantly influences their cellular uptake pathways. In vitro tests conducted on epithelial cell lines demonstrated that cubosomes were the most efficient delivery mechanism, enhancing cellular entry rates markedly.

Cubosomes, formed from the self-assembly of lipids in water, possess intricate structures with water channels and lipid bridges throughout. This unique configuration not only allows for the packaging of small molecule drugs but also enables them to enter cells through less conventional methods, such as direct fusion with the cell membrane. As Yap explains, "Cubosomes can bypass the cellular barriers that usually degrade nanoparticles, allowing for a more efficient delivery mechanism."

The research was supervised by RMIT's Distinguished Professor Calum Drummond AO, alongside Professors Charlotte Conn and Nhiem Tran, and represents a collaboration with Osaka University. The study utilized advanced facilities, including the Australian Synchrotron and various research laboratories at both institutions.

The findings of this study are poised to significantly impact the design of lipid nanoparticles for drug delivery, potentially improving therapeutic outcomes in various diseases. Future research aims to evaluate how these structured nanoparticles behave within biological systems and whether they can be tailored for specific tissues or diseases, thereby enhancing targeted therapies.

In conclusion, the discovery that cubosomes can enter cells through multiple pathways opens new avenues for the development of more efficient drug delivery systems. This research not only paves the way for improved mRNA therapies but also contributes to the broader field of nanomedicine, which aims to overcome the challenges associated with conventional drug delivery methods. As the scientific community continues to explore these advancements, the potential for innovative treatments becomes increasingly tangible.