Researchers Develop Method to Deliver Antibodies Inside Cells, Opening New Treatment Possibilities
Antibody-based therapies have revolutionized medicine, treating cancer, autoimmune, and inflammatory diseases by precisely targeting biological molecules. However, a major limitation is antibodies’ inability to penetrate inside cells, where many disease-related proteins reside. This challenge is compounded in the brain due to the blood-brain barrier, restricting drug access to the central nervous system.
A new study published in PNAS by researchers from Tel Aviv University, Cornell University, and the Technion introduces an innovative approach to temporarily "cloak" antibodies, enabling their packaging into lipid nanoparticles (LNPs), similar to those used in mRNA COVID-19 vaccines. The team developed a synthetic molecule named SL4 that binds antibodies and alters their chemical properties temporarily, allowing efficient encapsulation in LNPs. Once inside the cell, the antibody sheds this cloak and regains its original structure and function.
The encapsulation efficiency improved dramatically from about 4.4% for regular antibodies to 53.8% with SL4 cloaking. The researchers tested antibodies targeting key intracellular signaling pathways involved in cancer and inflammation, demonstrating successful cellular delivery and biological activity.
One notable application was in a Parkinson’s disease model, where an antibody against alpha-synuclein, a protein that abnormally accumulates in neurons, was delivered via LNPs. This treatment significantly reduced pathological protein aggregates in nerve cells. Although this is a preclinical study and not yet a therapy for Parkinson’s, it shows the potential to target intracellular disease mechanisms previously inaccessible to antibody drugs.
The approach was also tested in an acute lung inflammation model, where antibody delivery reduced inflammation markers and improved lung tissue pathology. The platform’s versatility suggests it could enable intracellular delivery of various antibodies for multiple diseases.
The researchers emphasize that while promising, this technology requires further safety, dosage, efficacy, and clinical testing before human treatments can be developed. The study was led by Christopher Alabi (Cornell) with contributions from Prof. Avi Schroder (Technion), Prof. Ben Maoz, and Prof. Uri Ashery (both Tel Aviv University). This method could expand the therapeutic targets accessible to antibody drugs by overcoming the barrier of cellular entry.
