Mount Sinai researchers develop blood-brain barrier breakthrough for drug delivery

Scientists at the Icahn School of Medicine at Mount Sinai have engineered a way to slip large therapeutic molecules past one of the body's most formidable barriers—the blood-brain barrier—using a technique that could reshape how doctors treat Alzheimer's disease, ALS, and dozens of other neurological conditions that have long resisted treatment.

The blood-brain barrier is evolution's security system. It protects the brain from toxins and pathogens, but it also blocks nearly everything else, including most drugs. This has created a cruel paradox in medicine: the diseases that damage the brain are often the hardest to treat because the medicines that might help cannot reach their target. Researchers have struggled with this problem for decades. Now, a team led by Yizhou Dong and Eric Nestler has published a solution in Nature Biotechnology.

The approach relies on a biological process called γ-secretase-mediated transcytosis—essentially, hijacking a natural cellular mechanism that the brain already uses to move molecules across the barrier. The researchers created what they call a blood-brain barrier-crossing conjugate, or BCC, a kind of molecular ferry that can carry large biomolecules, including oligonucleotides and proteins, directly into the brain through a simple intravenous injection. The compound they tested most extensively, called BCC10, proved remarkably effective.

In mouse models engineered to develop ALS, a devastating motor neuron disease, BCC10 linked to antisense oligonucleotides successfully reduced levels of Sod1, the gene that drives the disease, along with its associated protein. In a separate experiment, a different oligonucleotide attached to BCC10 significantly lowered Mapt, the gene that produces tau protein—a hallmark of Alzheimer's disease and related dementias. The researchers also tested the system on samples of human brain tissue removed during surgery and preserved in the laboratory, and it worked there too. Critically, the treatment caused little to no damage to major organs in the mice at the doses tested, suggesting it could be safe enough for human use.

Dong, a professor of immunology and immunotherapy at Mount Sinai, described the breakthrough in measured terms: the platform breaks through the barrier, allowing large biomolecules to reach the central nervous system safely and efficiently. Nestler, who directs the Friedman Brain Institute, framed it as a potential solution to one of neuroscience's most persistent obstacles—getting therapeutic molecules past the brain's defenses without harming the patient.

The work represents a shift in how researchers think about drug delivery to the brain. Rather than trying to force molecules through the barrier or surgically bypass it, the Mount Sinai team found a way to work with the brain's own transport systems. This is a distinction that matters. It suggests the approach could be adapted for many different diseases and many different therapeutic molecules, not just the ones tested here.

The next phase is already planned. The researchers will move to studies in larger animals—primates or other mammals closer in size and physiology to humans—to confirm that the system works as well outside the laboratory as it did in mice and tissue samples. If those studies succeed, the path toward human trials becomes clearer. The diseases waiting for this technology are numerous: Alzheimer's, Parkinson's, ALS, addiction, multiple sclerosis, and others. For patients and families living with these conditions, a working solution to the blood-brain barrier problem could mean the difference between a disease that progresses unchecked and one that can finally be treated.