An Ultrasmall Self‐Assembled Gallic‐Acid‐Based Natural Multifunctional Defense Networks for Therapeutic Application in Calcium Oxalate Nephropathies

Abstract Kidney stones, which have high prevalence and recurrence rates, often cause severe oxidative damage and inflammation. The ultrasmall hydrodynamic diameter of nanoparticles is crucial for their enrichment in the kidneys to exert biological activity. However, integrating crystallization inhibition and therapeutic functions into a single ultrasmall nanoparticle is challenging. A novel ultrasmall iron (Fe)–gallic acid (Ga) metal–phenolic networks (Fe–Ga MPNs) is developed for treating calcium oxalate (CaOx) nephropathies. These MPNs can specifically adsorb on the high‐energy () crystal face to inhibit the growth of CaOx monohydrate (COM), promoting the phase transition from highly toxic COM to low‐risk CaOx dihydrate. Fe–Ga MPNs have broad‐spectrum free radical scavenging abilities, reducing oxidative damage and inhibiting cell apoptosis. They exhibit sensitivity toward kidney damage, accumulating in injured renal tissue, reducing tubule injury and inflammation, improving tubule function, and inhibiting crystal formation. Fe–Ga MPNs also inhibit pro‐inflammatory macrophage polarization and upregulate anti‐inflammatory and highly phagocytic macrophage polarization. RNA sequencing analysis shows that Fe–Ga MPNs induce transcriptomic changes mainly involving immune regulation and citrate homeostasis pathways. In conclusion, the multifunctional nanonetwork Fe–Ga MPNs, with crystallization inhibition, antioxidant, and immune regulation properties, show great potential in treating CaOx nephropathies.