<p>Kidney stones are among the most common renal diseases with high global incidence and recurrence rates, with calcium oxalate (CaOx) stones constituting 65.9% to 80% of all cases. Minimally invasive surgery remains the primary approach for kidney stones, while limited progress has been made in the drug therapy for CaOx kidney stones over the recent years. The limitations of traditional drug therapy, such as renal toxicity and poor targeting, along with an elusive pathogenesis of CaOx kidney stones, have prevented its widespread clinical application. Renal tubular epithelial cells injury has been reported to play a crucial role in the occurrence and development of CaOx kidney stones. Nanozymes with potent antioxidant and anti-inflammatory properties have the potential to treat CaOx crystal-induced kidney injury. Moreover, as a key stone inhibitor, potassium citrate is widely used to inhibit stone formation due to its ability to modify urinary chemistry. Herein, we designed citrate-coated Prussian blue nanozyme hitchhiking on the neutrophils (NM@CPBzyme) with injured kidney targeting capability and good biosafety. The results showed that NM@CPBzyme alleviated CaOx crystal-induced kidney injury and CaOx crystals deposition. On the one hand, NM@CPBzyme has been demonstrated to not only suppress oxidative stress but also chelate calcium ions, thereby facilitating crystal dissolution. On the other hand, NM@CPBzyme could mitigate neutrophil infiltration, NETosis and inhibit pyroptosis in vitro and in vivo. In addition, RNA sequencing and bioinformatic analysis further showed that NM@CPBzyme ameliorates CaOx crystal-induced kidney injury via oxidative stress and neutrophil mediated inflammatory response. In summary, our results revealed that NM@CPBzyme is a novel strategy for protecting against CaOx crystal-induced kidney injury.</p> Graphical Abstract <p></p>