Protein Cloaking Breakthrough: Lipid Nanoparticles Revolutionize Intracellular Delivery

Researchers at Cornell have devised a new way to "cloak" proteins so that lipid nanoparticles can take them and send them into living cells, where they can work as medication.

This new method appears to transform the delivery of protein-based medicines, potentially leading to increased medical research and treatment applications.

Collaborative Innovation Transforms Protein Delivery

The research, published in the journal ACS Central Science, is titled "Bioreversible Anionic Cloaking Enables Intracellular Protein Delivery with Ionizable Lipid Nanoparticles." Azmain Alamgir, a doctoral student at Cornell University, led the group effort.

Chris Alabi, an associate professor of chemical and biomolecular engineering, and Matt DeLisa, a professor of engineering and head of the Cornell Institute of Biotechnology, took charge of the project.

They aimed to combine DeLisa's knowledge of making protein-based medicines and Alabi's focus on getting biologics into cells. While proteins are particular and often less harmful than small molecules, they are hard to send inside cells because they are so big and complicated.

Proteins can't quickly get into cells like small molecules can, which limits their use as medicines. This has long been an issue when making and using protein-based drugs.

The experts devised a bioconjugation method to solve this problem. Covering proteins with negatively charged ions could make proteins behave like nucleic acids, which naturally combine with positively charged lipids to form nanoparticles.

The successful COVID-19 vaccines produced by Pfizer-BioNTech and Moderna included these lipid nanoparticles, which inspired researchers to use this technology to deliver proteins.

Alamgir says their method is straightforward: they change the surfaces of proteins by adding negative charges, making them look like nucleic acids. Therefore, these proteins can form nanoparticles when mixed with specific lipids.

Practical Application and Testing Yield Promising Results

Developing proficiency in this method was not easy. Proteins cannot form lipid-nucleic acid complexes because the conditions are too harsh.

To get around this problem, the study team changed the formula by using milder conditions and adding more lipids. This led to an excellent way to cover proteins with lysine-reactive sulfonated compounds, which made it possible for therapeutic proteins to get into cells more effectively.

To show that their method worked, the team successfully delivered ribonuclease A to kill cancer cells and used monoclonal immunoglobulin G (IgG) antibodies to stop tumors from sending signals. Because the bioconjugation chemistry is reversible, the masking tag falls off as soon as the protein enters the cell's cytoplasm.

Because they are so flexible, cells can use many different proteins differently. Alamgir highlighted the potential for novel applications of off-the-shelf proteins within cells, which are available from various life science wholesalers and biotechnology companies.

What this breakthrough entails is critical. More efficient delivery of protein-based therapies into cells creates new avenues for cellular illness treatment. Furthermore, it simplifies the application of protein drugs such as antibodies, significantly broadening their therapeutic range.

The National Institutes of Health T32 Chemical Biology Interface training program, the Cornell Ignite Innovation Acceleration program, and the Chemical and Biomolecular Engineering Fleming Fellowship program helped the study. The DeLisa and Alabi labs' work together shows how powerful interdisciplinary study can be for making scientific and medical progress.

Experts at Cornell have developed a new cloaking method at the forefront of intracellular protein delivery advancements. This method not only enhances the efficacy of protein-based drugs but also paves the way for novel treatments that could significantly impact the future of medicine and transform the treatment of diseases at the cellular level.

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