<p>Selectively targeting
cell nucleolus remains a challenge. Here we report the first case that
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 cell nucleolus.
Structural analogue of the D-peptide reveals that particle morphology of the
assemblies, which depends on the side chain modification, favors the cellular
uptake. Contrasting 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.</p>
