Framework nucleic acids as structural nanomedicine for alleviating multi-organ injury in sepsis

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality worldwide. Effective therapeutic intervention is hampered by the poor pharmacokinetics and inadequate organ accumulation of conventional small-molecule drugs. Here, we report that DNA origami-based framework nucleic acids (FNAs) themselves function as a therapeutic structural nanomedicine for sepsis treatment. FNAs with rectangular, triangular, and tubular shapes efficiently scavenge reactive oxygen species (ROS) and promote macrophages toward an M2-like phenotype, thereby downregulating pro-inflammatory cytokines while upregulating the anti-inflammatory cytokines. Notably, the intrinsic structural properties of FNAs not only facilitate their accumulation in multiple organs but also sustain their retention for over 24 h. When systemically administered to lipopolysaccharide (LPS)-induced septic mice, FNAs remarkably improved the 72-hour survival rate to 100%, showing robust therapeutic efficacy. Our results demonstrate that FNAs can serve as a versatile therapeutic structural nanomedicine for ameliorating multi-organ injury in sepsis and potentially for other antioxidant therapies.