Oral Covalent Organic Frameworks as Dysbiosis‐Mitigating Oxalate Sequestrants for Crystalline Nephropathy

Abstract Hyperoxaluria‐related crystalline nephropathy progresses through a dynamic interplay among oxalate crystallization, renal inflammatory cascades, and gut dysbiosis. However, concurrent interventions for these interconnected pathways remain elusive. Here, we leverage the gut‐kidney axis to address this multifaceted renal issue by employing cationic covalent organic frameworks (COFs) as dysbiosis‐mitigating oxalate sequestrants. Oxalate adsorption assays and density functional theory calculations identify the HCl‐activated pyridine‐functionalized COF1‐Cl with superior oxalate adsorption capacity (94.5 mg g −1 ) and selectivity. Oral administration of COF1‐Cl in a rat model of hyperoxaluria effectively sequestrates oxalate within the gut and facilitates the transcellular secretion of serum oxalate into the intestinal lumen by upregulating the oxalate transporter (SLC26A6), resulting in decreased urinary oxalate excretion. Oxalate sequestration by COF1‐Cl restores the gut microbiota diversity and promotes the rebalance of typical bacteria associated with oxalate metabolism, stone formation risk, and immune homeostasis. This local gut effect inhibits renal oxalate crystal deposition and NLRP3 inflammasome activation, resulting in amelioration of renal function as evidenced by improved glomerular filtration and decreased blood creatinine and urea nitrogen levels. COF1‐Cl also demonstrates good biosafety due to its inert and nonabsorbable nature. This work highlights the potential of utilizing a gut‐restricted porous crystalline framework to address metabolism‐driven pathology via gut‐organ crosstalk.