Background <p>Sepsis is a life-threatening infectious disease characterized by an uncontrolled inflammatory response and consequent multi-organ dysfunction. The kidneys, as primary excretory organs with high blood flow, are particularly susceptible to damage during sepsis. Nonetheless, the existing treatment options for sepsis-associated acute kidney injury (SA-AKI) are still restricted. Nanomedicine, especially carbon dots (CDs), has attracted considerable interest lately for outstanding biomedical characteristics.</p> Methods <p>To avoid the generation of toxic effects, the natural CDs derived from <i>Ziziphi Spinosae Semen</i> (Z-CDs) were synthesized employing a hydrothermal method. The free radical scavenging capabilities of Z-CDs were evaluated by utilizing ABTS assay, NBT method, and Fenton reaction. A lipopolysaccharide (LPS)-stimulated RAW 264.7 cell model was used to explore the therapeutic potential of Z-CDs on cellular oxidative stress and inflammation. The CuSO₄-induced zebrafish inflammation model and LPS-exposed SA-AKI mouse model were employed to assess the therapeutic efficacy of Z-CDs in vivo.</p> Results <p>The synthesized Z-CDs exhibited distinctive unsaturated surface functional groups, which confer exceptional biocompatibility and the ability to scavenge free radicals. Moreover, Z-CDs were particularly effective in eliminating excess reactive oxygen species (ROS) in cells, thus protecting mitochondrial function from oxidative damage. Notably, Z-CDs have demonstrated significant therapeutic benefits in protecting kidney tissue in SA-AKI mouse model with minimizing side effects. In mechanism, Z-CDs effectively reduced ROS production, thereby alleviating inflammatory responses in macrophages through the suppression of the NF-κB pathway.</p> Conclusions <p>This study developed a multifunctional nanomedicine derived from traditional medicinal herb, providing a promising pathway for the advancement of innovative drug therapies to treat SA-AKI.</p>