Emerging Role of Noncovalent Interactions and Disulfide Bond Formation in the Cellular Uptake of Small Molecules and Proteins

Intracellular delivery of proteins and small molecules is an important barrier in the development of strategies to deliver functional proteins and therapeutics into the cells to realize their full potential in biotechnology, biomedicine, cell-based therapies, and gene editing protein systems. Most of the intracellular protein delivery strategies involve the conjugation of cell penetrating peptides to enable the permeability of plasma membrane of mammalian cells to allow proteins to enter cytosol. The conjugations of small molecules such as (p-methylphenyl) glycine, pyrenebutyrate and cysteines are used for the same purpose. Molecular level interactions are governed mostly by ionic (cationic/anionic), covalent and noncovalent interactions with various molecular entities of glycocalyx matrix on plasma membrane lipid bilayer. Although the role of noncovalent interactions in cellular uptake is not fully understood, several recent advances have focused on the noncovalent interaction-based strategies of intracellular delivery of small molecules and proteins into mammalian cells. These are achieved by simple modification of protein surfaces with chemical moieties which can form noncovalent interactions other than hydrogen bonding. In this review, we describe the recent advances and the mechanistic aspects of intracellular delivery and role of noncovalent interactions in the cellular uptake of proteins and small molecules.