Intracellular Delivery of Adamantane-Tagged Small Molecule, Proteins, and Liposomes Using an Octaarginine-Conjugated β-Cyclodextrin

Herein, we demonstrate a convenient technique for the intracellular delivery of proteins and liposomes based on supramolecular host-guest chemistry. First, we prepared the R8-CDOH carrier molecule, which is a ss-cyclodextrin derivative bearing an octaarginine (R8) chain, as a cellpenetrating peptide, at the primary hydroxyl group. The surface amino groups of proteins (GFP, ss-gal, and IgG) were then partly modified with adamantane (Ad) tags using 1-Ad-carboxylic acid N-hydroxysuccinimide ester (Ad-NHS). These Ad-tagged proteins were effectively delivered into HeLa cells though supramolecular host-guest interactions with R8-CDOH. A 100 nm sized liposome bearing Ad-tags on its surface was also delivered into these cells by the action of R8-CDOH. The present method does not require any genetic manipulation, and only easy chemical modification processes are used to facilitate intracellular delivery; therefore, we believe that the present method is applicable to a variety of bioengineering processes, such as protein-based therapeutics, cellular reprogramming, and genome-editing, among others.