Redox-responsive nanoparticles for enhanced mRNA delivery: a comprehensive review

The clinical success of mRNA vaccines during the COVID-19 pandemic highlighted the therapeutic potential of mRNA while exposing persistent delivery barriers, including intrinsic instability, poor cellular uptake, and inefficient intracellular trafficking. Redox-responsive nanoparticles (NPs) provide a promising strategy to improve mRNA delivery by undergoing stimulus-triggered disassembly in the reductive cytosol, facilitating efficient mRNA release, endosomal escape, and enhanced translation. This review elucidates emerging structure-function relationships by systematically linking redox-labile chemistries (e.g., disulfide, diselenide, and polysulfide), carrier type, and NP architecture to key biological outcomes, including endosomal escape, redox responsiveness, transfection efficiency, and biodistribution. We further identify critical translational challenges-such as tumor redox heterogeneity, insufficient systematic preclinical evaluation, and manufacturing constraints-and propose actionable strategies, including multi-stimulus-responsive systems, microfluidic and process-analytical manufacturing, and formulation approaches to improve efficacy, reproducibility, and stability. Collectively, these insights provide a practical framework to guide the rational design and clinical translation of next-generation redox-responsive mRNA delivery platforms.