Over the past few decades, antibody-based therapies have revolutionized modern medicine and are now widely used to treat cancer, autoimmune diseases, inflammatory disorders, and even infectious diseases. Despite their success, however, antibodies have a significant limitation: they struggle to penetrate cells and are therefore largely limited to targeting molecules located on the cell surface or outside the cell. In addition, antibody-based drugs have difficulty crossing the blood-brain barrier, restricting their use in treating diseases such as Parkinson’s and Alzheimer’s. Now, researchers at Tel Aviv University, together with colleagues, have developed a new technology that could overcome these barriers, enabling antibodies to reach the most important targets, those located inside the cell itself.
The technology was developed through a collaboration between research groups from Cornell University in the United States, Tel Aviv University, and the Technion. The study was led by Prof. Chris A. Alabi and Prof. Matthew P. DeLisa from Cornell, collaborating with Prof. Avi Schroder from the Technion and TAU’s Prof. Ben Maoz of the Fleischman Faculty of Engineering and the Sagol School of Neuroscience and Prof. Uri Ashery of the Wise Faculty of Life Sciences and the Sagol School of Neuroscience, together with Prof. Christopher Alabi of Cornell. The findings were published in the Proceedings of the National Academy of Sciences (PNAS) .
In the study, the researchers developed an innovative approach based on temporarily “masking” the antibody using a synthetic molecule called SL4. This masking alters the antibody’s chemical properties in a controlled manner, allowing it to be encapsulated in lipid nanoparticles (LNPs), similar to the technology used to develop mRNA vaccines against COVID-19. Once the nanoparticles enter the cell, the antibody is released and regains its original structure and activity.
According to the researchers, this represents a significant breakthrough because approximately 80% of the proteins involved in human disease are located inside cells, making them inaccessible to most antibody-based therapies. The ability to deliver active antibodies into the cell cytoplasm opens new possibilities for treating diseases that have long been considered inaccessible to drug-based interventions.
The study demonstrated that the masking process significantly improves the efficiency with which antibodies can be encapsulated within lipid nanoparticles. Whereas unmodified antibodies were incorporated into the nanoparticles with relatively low efficiency, the masked antibodies achieved substantially higher encapsulation rates while retaining their stability and their ability to recognize the molecular target associated with the disease.
The researchers tested the technology using a series of therapeutic antibodies targeting key biological pathways involved in disease development. The antibodies successfully entered cells and altered important signaling pathways associated with various types of cancer and inflammatory diseases. Following treatment, the activity of these pathways was significantly reduced, indicating that the antibodies had reached their intended targets and remained active inside the cells.
One of the study’s most promising findings emerged from a research model of Parkinson’s disease. The researchers used an antibody targeting alpha-synuclein, a protein whose accumulation in the brain is one of the hallmarks features of the disease. Following delivery of the antibody via the nanoparticles, they observed a significant reduction in the pathological aggregates of the protein in nerve cells, a finding that suggests that the technology could pave the way for new treatments for neurodegenerative diseases.
The technology was also evaluated in a model of acute inflammatory lung injury. The researchers found that delivering antibodies via the lipid nanoparticles reduced inflammatory markers and improved pathological features of lung tissue. These findings highlight the potential for developing targeted therapies for severe inflammatory conditions.
Prof. Ben Maoz said: “For many years, delivering antibodies into cells has been considered one of the greatest challenges in the field of biologic therapies. We have succeeded in developing a system that enables antibodies to cross the cellular barrier and reach targets that were previously beyond their reach. We believe this is an important step toward expanding the therapeutic toolbox of modern medicine and paving the way for more precise treatments for complex diseases that still lack adequate therapeutic solutions.”
The researchers emphasize that the technology is still at the preclinical stage. Nevertheless, they believe the platform could lay the foundation for a new generation of biologic therapies. If it successfully progresses through development and clinical trials, it could, for the first time, enable the widespread use of antibodies against intracellular targets, a goal widely regarded in the pharmaceutical industry as the next frontier of personalized medicine.
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