Researchers Develop New LNP to Successfully Deliver mRNA to The Brain

The blood-brain barrier (BBB) refers to the barrier between plasma and brain cells formed by the walls of brain capillaries and glial cells, and the barrier between plasma and cerebrospinal fluid formed by the choroid plexus, which only allows specific types of molecules to enter brain neurons and other surrounding cells from the bloodstream. The existence of the blood-brain barrier is of great significance in preventing harmful substances from entering the brain from the blood. However, it also prevents the transfer of most small and large molecule drugs (such as peptides, proteins and nucleic acids), severely limiting the treatment of central nervous system diseases (such as neurodegenerative diseases, brain tumors, brain infections and strokes). Although some progress has been made in this field in recent years, we still urgently need technologies that can cross the blood-brain barrier and improve the delivery of biomacromolecule-based therapies to the central nervous system (CNS) through systemic administration.

In February 2025, Professor Yizhou Dong's team at the Icahn School of Medicine at Mount Sinai published a research paper titled "Blood-brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system" in Nature Materials, a Nature journal. The study developed a new lipid nanoparticle (LNP) system, MK16 BLNP, which can break through the blood-brain barrier and deliver mRNA to neurons and astrocytes in the brain's central nervous system through intravenous injection. The study paves the way for future treatments of a range of brain diseases such as Alzheimer's disease, ALS, brain tumors, and drug addiction.

Previously, researchers developed a γ-secretase-mediated blood-brain barrier coupling (BCC) system that can cross the blood-brain barrier. Biomacromolecules (such as oligonucleotides) can be safely and effectively delivered to the central nervous system (CNS) through intravenous injection, and gene silencing can be performed on mouse models and human brain tissue. In a new study published in Nature Materials, Professor Dong Yizhou's team tried to develop a new LNP that can deliver mRNA to the brain's central nervous system, allowing mRNA to enter the brain and instruct brain cells to produce therapeutic proteins. These proteins can help treat or prevent diseases by replacing missing proteins, reducing harmful proteins, or activating the body's defenses.

The research team designed and synthesized six categories of 72 lipids (BL) that can cross the blood-brain barrier (BBB), including L-DOPA derivatives, D-serine derivatives, temozolomide derivatives, tryptamine derivatives, cinnamic acid derivatives, and MK-0752 derivatives. These lipids are formed by combining BBB-spanning modules with amino lipids. Through screening and structural optimization, the research team obtained a leading blood-brain barrier lipid nanoparticle (BLNP) - MK16 BLNP, which can significantly improve the efficiency of mRNA delivery to the brain.

Figure 1. Illustration of the formulation of BLNPs and potential BBB-crossing mechanisms. (Wang C, et al., 2025)

The research team further revealed that MK16 BLNP crosses the blood-brain barrier through transcellular effects mediated by caveolae and γ-secretase. It was verified in multiple mouse models, and the results showed that MK16 BLNP can deliver mRNA to neurons and astrocytes throughout the brain through intravenous injection. It also showed good tolerability under multiple dosage regimens, and can effectively treat drug addiction in mice, as well as significantly improve the survival rate of glioblastoma mouse models. In addition, these BLNPs can also deliver mRNA to ex vivo human brain samples.

In general, this study designed and synthesized a series of lipid nanoparticles (BLNPs) that can cross the blood-brain barrier and efficiently deliver mRNA to neurons and astrocytes in the brain. In particular, MK16 BLNPs, which cross the blood-brain barrier through transcellular action mediated by caveolin and γ-secretase, show good tolerability and broad application prospects. This study provides a promising platform for delivering mRNA to the central nervous system, which is expected to open up new avenues for the treatment of various brain diseases.