Redox-responsive peptide folding enables intracellular self-assembly and controlled nucleic acid release

Area of Science:

• Biomaterials Science
• Molecular Biology
• Drug Delivery Systems

Background:

• Intracellular peptide self-assembly offers spatiotemporal control over biomolecular interactions.
• Existing systems often use irreversible triggers, limiting dynamic regulation of cellular processes.

Purpose of the Study:

• To develop a reversible, redox-responsive peptide system for controlled intracellular delivery of nucleic acids.
• To establish a generalizable design principle for stimulus-responsive biomaterials.

Main Methods:

• Design and synthesis of a redox-responsive amphiphilic peptide with an intramolecular disulfide bond.
• Utilizing structural, biophysical, and cellular imaging analyses to confirm peptide behavior.
• Demonstrating the three-step, reduction-responsive, assembly and release (RAR) mechanism.

Main Results:

• The peptide switches between disordered coil and β-hairpin conformations in response to redox conditions.
• The peptide efficiently complexes with nucleic acids and penetrates cells in its oxidized state.
• Intracellular reduction triggers peptide self-assembly into nanofibrils and releases nucleic acid cargo.

Conclusions:

• The developed RAR mechanism enables efficient and spatiotemporally controlled intracellular delivery.
• The reversible and programmable peptide platform serves as a generalizable design for stimulus-responsive biomaterials.
• This approach advances nucleic acid therapeutics through dynamic intracellular control.