Nanodiamond‐Based Platform for Intracellular‐Specific Delivery of Therapeutic Peptides against Hepatocellular Carcinoma

Abstract Therapeutic peptides are attractive as a treatment modality due to their high selectivity and relative safety and tolerability. Delivery of therapeutic peptides to target cells continues to pose a challenge, particularly when these peptides target intracellular proteins. In this study, the use of nanodiamonds (NDs) as a platform for enhanced intracellular delivery of therapeutic peptides is investigated. SALL4 is found to contribute to tumor progression in many types of cancers, including hepatocellular carcinoma (HCC). Therapeutic peptides specifically targeting SALL4 demonstrate an effective, but limited, inhibitory effect on SALL4‐driven HCC tumor cell growth. Nanodiamond‐based delivery of SALL4‐inhibitory peptides is found to improve peptide stability and cellular peptide retention. Stimuli‐responsive release of SALL4‐inhibitory peptide from nanodiamonds ensures intracellular‐specific delivery of functional SALL4‐inhibitory peptides. The observed enhanced peptide stability and intracellular‐specific delivery of SALL4‐inhibitory peptides by nanodiamonds result in improved therapeutic efficacy by ND‐peptide complexes against SALL4‐driven HCC. As such, nanodiamonds serve as a promising platform for stimuli‐responsive intracellular‐specific delivery of therapeutic peptides.