Bionic Black Phosphorus Nanosheets Confer Dual Protection against Nephrocalcinosis-Induced Kidney Injury via ROS Scavenging and NETosis Inhibition

Calcium oxalate (CaOx) nephrocalcinosis is a chronic kidney disease marked by CaOx crystal deposition, oxidative stress, neutrophil infiltration, and renal tubular epithelial cell injury. To date, no targeted therapies are clinically available for this condition. Antioxidant nanomaterials capable of scavenging excessive reactive oxygen species (ROS) offer a promising approach for treating CaOx crystal-induced kidney injury. Neutrophil-mediated delivery systems have been leveraged to transport nanomaterials to inflamed kidneys for acute kidney injury therapy, and their targeting specificity can be further augmented through the functionalization of cell membranes with targeting peptides. Herein, we developed a biomimetic nanoplatform by loading DNase I onto black phosphorus nanosheets (BPNSs) and coating them with a neutrophil membrane modified with a CD44-targeting peptide (PNM@D@BP), aiming to ameliorate renal CaOx crystal deposition and the consequent kidney injury. The engineered neutrophil membrane coating conferred the nanocarrier with the ability to home to sites of renal injury and inflammation. PNM@D@BP exhibited potent antioxidative activity, effectively eliminating CaOx crystal-induced ROS. In both in vivo and in vitro settings, PNM@D@BP was shown to suppress the formation of neutrophil extracellular traps (NETs). Moreover, RNA sequencing and bioinformatic analyses revealed that PNM@D@BP protects against CaOx crystal-induced kidney injury by modulating oxidative stress and neutrophil-driven inflammatory responses. Collectively, these findings underscore the therapeutic potential of PNM@D@BP for the treatment of CaOx kidney stones.