Assemblies of d-Peptides for Targeting Cell Nucleolus

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• Targeting the cell nucleolus selectively is a significant challenge in cellular biology and drug delivery.
• Developing novel strategies for subcellular organelle targeting is crucial for advancing therapeutic interventions.

Purpose of the Study:

• To investigate the potential of d-peptides in forming targeted molecular assemblies for nucleolar delivery.
• To explore the mechanism of d-peptide self-assembly and cellular uptake for organelle-specific accumulation.

Main Methods:

• Synthesis and characterization of d-peptide derivatives and their self-assembled nanoparticles.
• Cellular uptake studies using fluorescence microscopy and confocal imaging.
• Investigation of subcellular localization (nucleolus vs. lysosomes) of d-peptide assemblies.
• Preliminary mechanistic studies on RNA interaction and induction of DNA damage.

Main Results:

• D-peptide derivatives self-assemble into nanoparticles that are preferentially internalized via clathrin-dependent endocytosis.
• These nanoparticles predominantly accumulate in the cell nucleolus, unlike their l-enantiomer counterparts which localize in lysosomes.
• The morphology of d-peptide assemblies, influenced by side chain modifications, impacts cellular uptake efficiency.
• D-peptide nanoparticles interact with RNA to form membraneless condensates within the nucleolus.

Conclusions:

• D-peptides can be rationally designed to form supramolecular assemblies targeting the cell nucleolus.
• Formation of RNA-d-peptide condensates in the nucleolus induces DNA damage and subsequent cell death.
• This study presents a novel strategy for designing d-peptide-based supramolecular systems for specific organelle targeting.