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Redox-responsive peptide assemblies for precision theranostic
Soheil Haddadzadegan1, Congxi Huang1, Mahsa Ghafouri1
1Center for Sustainable Materials (SusMat), School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore.
Abstract:
Redox biology represents a universal molecular language that encodes biochemical gradients, distinguishing healthy from diseased tissues with significant precision. The convergence of redox signaling and peptide self-assembly results in a versatile chemical framework for next-generation theranostics. Peptides, programmable, biocompatible, and hierarchically organized, can translate subtle oxidative cues into structural transitions, functional activation, and real-time diagnostic output. Redox-responsive molecular assemblies leveraging disulfide exchange, thiol oxidation, methionine sulfoxidation, and dithiane chemistry enable dynamic assembly, phase transition, or disintegration based on local redox potential. Redox dysregulation, encompassing reactive oxygen species and reactive nitrogen species imbalance, glutathione depletion, and iron-driven lipid peroxidation - governs diverse pathologies from cancer to neurodegeneration. In parallel, beyond traditional delivery platforms, redox-activated phase-separating peptides forming coacervate microdroplets have emerged as versatile drug vectors with high-capacity recruitment of nucleic acids, proteins, and small molecules, with cytosolic release triggered by glutathione. These condensate-like materials exhibit rapid and very high encapsulation efficiency, intracellular uptake, and redox-coded responsiveness. Additionally, imaging probes coupling redox-triggered bond cleavage with optical or magnetic signal activation allow real-time visualization of redox landscapes during therapy. From a translational perspective, progress is accelerated by advances in large-scale solid-phase peptide synthesis, redox-stable manufacturing workflows, and evolving regulatory frameworks. Future redox-responsive peptide coacervates are envisioned as programmable "chemical processors" that sense oxidative flux, interpret biochemical input, and deliver microenvironments-specific outputs. Such adaptive, information-rich architectures position peptide-based redox nanotheranostics as an emerging class of biomaterials capable of combining therapeutic action with the dynamic redox logic of diseases.