Disorganized Nanoparticles May Be Key to More Effective Drug Delivery
Lipid nanoparticles (LNPs) – the technology that powered the success of mRNA COVID-19 vaccines – may be more effective when they are slightly disorganized, according to recent research from the University of Copenhagen. This finding challenges conventional wisdom in drug delivery, which has historically focused on maximizing the packing of medicine into each nanoparticle.
The Challenge of Drug Delivery Efficiency
A major hurdle in LNP-based therapies is the low efficiency of cargo release inside cells. Currently, only about 1-5% of the therapeutic substance carried by LNPs actually reaches its target within the cell. This limitation impacts the effectiveness of treatments, particularly in rapidly dividing cells like those found in cancer, where insufficient RNA delivery can allow the disease to outpace therapy.1
New Insights into Nanoparticle Structure
Researchers at the University of Copenhagen developed a high-throughput method to analyze individual nanoparticles, rather than relying on average batch properties. This allowed them to identify two distinct subpopulations of LNPs: those with a highly organized internal structure and those that are more amorphous or disorganized.1
Surprisingly, the disorganized particles demonstrated superior performance in delivering their cargo inside cells. The key lies in the interactions between the positively charged lipids and the negatively charged RNA within the nanoparticle. In organized particles, these charges are tightly bound, resisting release even when conditions change inside the cell. Though, in disorganized particles, some separation exists between the charges. This allows the positive charges to repel each other when encountering the cellular environment, causing the particle to break apart and release its therapeutic payload.1
Implications for Future Drug Development
These findings suggest that future LNP development should prioritize maintaining a degree of internal disorder to facilitate cargo release, rather than solely focusing on maximizing cargo quantity. “We’re aiming in the opposite direction of what the field has been pursuing,” explained Artu Breuer, PhD, a postdoctoral researcher in biophysics at the University of Copenhagen.1
The Role of Lipid Nanoparticles in Modern Medicine
LNPs have become a cornerstone of mRNA vaccine technology, notably in the fight against COVID-19.1 Beyond vaccines, they are being explored as delivery systems for treatments targeting cancer, rare genetic diseases and other conditions.1 Understanding the role of each lipid component in LNPs – including their impact on size, structure, stability, and cellular uptake – is crucial for optimizing their effectiveness.1
Safety Considerations
While LNPs have proven highly effective, safety concerns regarding potential immune responses to the nanoparticle components have been raised. Research has focused on antibodies against polyethylene glycol (PEG), a common coating on LNPs, which can sometimes induce allergic reactions.3 However, studies investigating the Comirnaty mRNA-based COVID-19 vaccine have not shown a significant increase in anti-LNP antibodies after two doses, suggesting the vaccine does not induce the generation of such antibodies.3
The research presented at the Biophysical Society Annual Meeting (February 21-25, 2026, San Francisco) offers a new perspective on optimizing LNP design for improved therapeutic outcomes.