Chemical Modification of Proteins and Their Intracellular Delivery Using Lipidoid Nanoparticles

Protein-based therapeutics are a class of drugs considered to be one of most safe and straightforward approaches for manipulating cell function and treating diseases. However, in contrast to traditional small-molecule drugs, most protein drugs cannot easily pass through biological membrane barriers due to their large size and surface chemistry. Consequently, most of the current FDA approved protein pharmaceuticals target secreted domains or cell surface-bound receptors, for which the drug does not need to pass through the cell membrane. Effective delivery systems that can transport functionally intact protein molecules to their intracellular targets can contribute to further expanding the therapeutic modalities of protein-based drugs. Furthermore, proteins themselves can be engineered, either to facilitate their interaction with the delivery system, or to improve their specificity and efficacy upon intracellular delivery. Both physical and biochemical methods have been developed for intracellular protein delivery and each strategy has its own advantages and drawbacks. We describe here the methods of chemical modification of therapeutic proteins in combination of the lipid-like molecules or lipidoids to enhance their intracellular delivery efficiency.