Assemblies of D-Peptides for Targeting Cell Nucleolus

Selectively targeting the cell nucleolus remains a challenge. Here, we report the first case in which D-peptides form membraneless molecular condensates with RNA for targeting cell nucleolus. A D-peptide derivative, enriched with lysine and hydrophobic residues, self-assembles to form nanoparticles, which enter cells through clathrin-dependent endocytosis and mainly accumulate at the cell nucleolus. A structural analogue of the D-peptide reveals that the particle morphology of the assemblies, which depends on the side chain modification, favors the cellular uptake. In contrast to those of the D-peptide, the assemblies of the corresponding L-enantiomer largely localize in cell lysosomes. Preliminary mechanism study suggests that the D-peptide nanoparticles interact with RNA to form membraneless condensates in the nucleolus, which further induces DNA damage and results in cell death. This work illustrates a new strategy for rationally designing supramolecular assemblies of D-peptides for targeting subcellular organelles.