Redox-responsive nanomaterials for mRNA delivery: From rational design to therapeutic applications

Messenger RNA (mRNA) therapeutics have emerged as a transformative biomedical platform with broad potential in vaccination, protein replacement, gene editing, and cancer immunotherapy. Despite substantial progress, the broader clinical translation of mRNA therapeutics requires further optimization of delivery systems to address challenges related to stability, biodistribution, intracellular delivery efficiency, and biosafety. In this review, we discuss the rational design of redox-responsive nanomaterials that exploit physiological intracellular redox compartmentalization or, in selected systems, disease-associated oxidative or reductive dysregulation to improve mRNA delivery. We first summarize the biological basis of redox-responsive delivery by linking disease-associated redox imbalance with the engineering principles of responsive nanomaterials. We then systematically discuss major classes of redox-responsive systems, including oxidation-responsive, reduction-responsive, and dual-responsive platforms across polymeric, lipid-based, and hybrid nanomaterial formulations. Particular emphasis is placed on how distinct chemical architectures and responsive motifs influence intracellular delivery behavior, cargo release, immune compatibility, and therapeutic performance. Finally, we discuss current translational challenges, including long-term biosafety, repeated administration, immunogenicity, and large-scale manufacturing, while highlighting emerging opportunities such as AI-assisted material design and personalized theranostic applications. Collectively, this review provides a comprehensive framework for understanding how redox-responsive nanomaterial engineering may advance the next generation of precise and clinically translatable mRNA therapeutics.