D4F‐Functionalized Ceria Nanozyme‐CasRx Platform Suppresses STING and Reprograms the Renal Immune Niche in Acute Kidney Injury

ABSTRACT Acute kidney injury (AKI) is sustained by reciprocal amplification of oxidative stress, innate immune signaling, and maladaptive immune–parenchymal crosstalk. Here, we developed a lipid nanoparticle containing a ceria nanozyme and a STING‐targeting CasRx plasmid and functionalized it with D4F, an 18‐residue apolipoprotein A‐I mimetic peptide composed of D‐amino acids. The resulting D4F‐CeO 2 @LNP‐CasRx(STING) formulation retained radical‐scavenging activity, supported CasRx encapsulation, and showed enhanced cellular and renal delivery. In macrophages, the formulation reduced oxidative stress and total STING abundance together with downstream TBK1 and IRF3 phosphorylation, shifted the CD86/CD206 profile toward a less inflammatory state, and altered the secretome in a manner that protected hypoxia‐challenged tubular epithelial cells. In kidney organoids and peripheral‐blood‐mononuclear‐cell‐coupled organoid cultures, D4F functionalization improved intratissue accumulation, increased the frequency of CD4 + FOXP3 + T cells, and attenuated the hypoxia‐associated DNA damage response and tubular injury. In mice with renal ischemia–reperfusion injury, treatment reduced STING signaling in CD11b + renal macrophages, improved renal function and histology, and lowered whole‐kidney inflammatory and injury readouts. Spatial transcriptomic and proteomic analyses were consistent with contraction of inflammatory immune states and restoration of repair‐associated programs. These findings support a DNA‐delivering nanozyme strategy for renal immune‐niche modulation in AKI.