Overcoming Liver Accumulation: Extrahepatic Targeting Strategies for Lipid Nanoparticles (LNPs)
One of the greatest challenges when using LNPs for drug delivery is their tendency to accumulate in the liver. Recent publications on this topic suggest strategies to reach targets beyond the liver and therefore boost the attractiveness of using LNPs.
The Challenge of Liver Tropism
Following intravenous injection, LNPs tend to accumulate in the liver. This is largely due to the interaction between LNP lipid components and apoliprotein E (ApoE), a protein that facilitates the uptake of low-density lipoproteins (LDLs) by hepatocytes. Consequently, the liver-specific accumulation reduces their bioavailability in other tissues or organs, leading to off-target effects and reduced therapeutic efficacy.
Achieving precise delivery to specific tissues or cells remains a significant obstacle. Unlike ApoE for lipoprotein, there are no universal proteins known for selective uptake to certain tissues. However, there are some promising strategies to overcome liver accumulation.
Strategies for Extrahepatic Delivery
There are three main approaches that can be employed individually or in combination to achieve extrahepatic delivery: passive targeting, active targeting, and endogenous targeting.
Passive targeting utilizes the unique anatomical and physiological characteristics of the target tissue to design LNPs that suit them. This involves adapting their size, charge, or shape to optimize accumulation in specific tissues. For example, the accumulation of nanoparticles in tumor tissue relies on the permeability of the tumor blood vessels (enhanced permeability and retention effect). Tumor blood vessels are more permeable than normal vasculature, allowing nanoparticles of a particular size to pass through the fenestrations between endothelial cells to accumulate in tumor tissue.
Active targeting involves modifying the surface of the LNP by attaching targeting ligands such as antibodies, antibody fragments, peptides, ligands etc. These ligands bind to a specific receptor on the target cell, facilitating receptor-mediated cellular uptake. For instance, antibody-linked LNPs can be used for delivering mRNA to reprogram T-lymphocytes in the heart – generating transient Chimeric Antigen Receptor T-cells (CAR T), state-of-the-art immunotherapy- against cardiac fibrosis.
The concept of endogenous targeting implies altering the chemical makeup of lipid nanoparticles to help them reach specific tissues in the body. Scientists do this by adding extra lipid components or using new types of lipids in the nanoparticle structure. Once injected into the bloodstream, these changes cause certain proteins to stick to the nanoparticles, forming a protective layer (called "biomolecular corona"). This layer then helps direct the nanoparticles to specific tissues outside the liver, like the bone marrow, spleen, or lungs.
For example, if the nanoparticles contain permanently positively charged SORT (selective organ targeting) lipids, they can be designed to deliver drugs specifically to the lungs. This happens because the positive charge attracts a particular protein, vitronectin, which helps the particles reach the lung tissue. On the other hand, permanently negatively charged SORT lipids on the nanoparticles can direct them to the spleen. Here, a different protein, β-2-glycoprotein I, forms the corona, guiding the nanoparticles to the spleen.
Another strategy proven to direct the nanoparticles to the spleen is using short-tail lipids. In fact, recent studies show that mRNA expression gradually shifts from the liver to the spleen depending on the ionizable lipid tail length.
The Horizon of LNP Development for Targeted Delivery
The challenge of liver tropism remains a significant barrier in the use of lipid nanoparticles (LNPs) for precise drug delivery. However, innovative strategies like passive targeting, active targeting, and endogenous targeting offer promising solutions to achieve extrahepatic delivery. From tailoring nanoparticle characteristics to leveraging ligand-receptor interactions and optimizing lipid chemistry, these approaches open exciting possibilities for enhancing therapeutic efficacy.
While many of these strategies show great promise, most still require clinical validation to prove their effectiveness. Ongoing LNP research is crucial to uncover innovative targeting mechanisms, and recent discoveries—such as the role of lipid tail length and selective organ targeting (SORT) lipids — highlight the potential of LNPs to revolutionize drug delivery systems. With continued advancements, LNPs could become indispensable tools for targeted drug delivery, unlocking new frontiers in precision medicine.
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