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

Abstract

Intracellular peptide self-assembly provides a powerful strategy for spatiotemporal control of biomolecular interactions, yet most existing systems rely on irreversible triggers, limiting dynamic regulation. Herein, we report a redox-responsive amphiphilic peptide with a strategically positioned intramolecular disulfide bond, enabling reversible switching between a disordered coil and a β-hairpin conformation. In oxidized state, the peptide efficiently complexes with nucleic acids and penetrates cells. Intracellular glutathione reduction cleaves the disulfide, inducing β-hairpin folding, which drives supramolecular self-assembly into nanofibrils and concomitantly releases nucleic acid cargo. This three-step, reduction-responsive, assembly and release (RAR) mechanism achieves efficient, spatiotemporally controlled intracellular delivery. Structural, biophysical, and imaging analyses confirm the redox-triggered conformational transition, intracellular assembly, and cargo dissociation. This reversible and programmable platform establishes a generalizable design principle for stimulus-responsive biomaterials and nucleic acid therapeutics.