Reactive oxygen species in lipid nanoparticle-based nucleic acid delivery: Mechanisms and engineering

Reactive oxygen species (ROS) play essential yet double-edged roles in lipid nanoparticles (LNP)-mediated nucleic acids delivery, influencing the entire delivery cascade from formulation and tissue distribution to intracellular trafficking and gene expression. ROS critically regulate lipid stability, nucleic acid integrity, endosomal escape, transfection efficiency, and immune activation. In this review, we summarize the spatiotemporal distribution of ROS across the LNP delivery lifecycle and discuss their mechanistic roles in key processes, including endosomal membrane damage and repair, nucleic acid delivery efficiency, inflammasome activation, and complement system responses. Based on these mechanistic insights, we categorize emerging ROS-based engineering strategies into three classes, including ROS-responsive, ROS-regulatory, and combinatorial approaches. ROS-responsive strategies exploit redox stimuli to trigger controlled cargo release, whereas ROS-regulatory strategies incorporate antioxidant lipids or other functional components to modulate intracellular redox homeostasis and preserve nucleic acid stability. Combinatorial strategies integrate modalities such as photodynamic, photothermal, or chemotherapeutic agents to balance delivery efficiency and biosafety. A comprehensive understanding of ROS-mediated regulation provides a rational framework for the design of next-generation LNPs with satisfactory therapeutically relevant expression efficiency and minimized toxicity.