Self-assembled hemin-conjugated heparin with dual-enzymatic cascade reaction activities for acute kidney injury

Abstract

Nanozymes have prominent catalytic activities with high stability as a substitute for unstable and expensive natural enzymes. However, most nanozymes are metal/inorganic nanomaterials, facing difficulty in clinical translation due to their unproven biosafety and limited biodegradability issues. Hemin, an organometallic porphyrin, was newly found to possess superoxide dismutase (SOD) mimetic activity along with previously known catalase (CAT) mimetic activity. However, hemin has poor bioavailability due to its low water solubility. Therefore, a highly biocompatible and biodegradable organic-based nanozyme system with SOD/CAT mimetic cascade reaction activity was developed by conjugating hemin to heparin (Hep-H) or chitosan (CS-H). Between them, Hep-H formed a smaller (<50 nm) and more stable self-assembled nanostructure and even possessed much higher and more stable SOD and CAT activities as well as the cascade reaction activity compared to CS-H and free hemin. Hep-H also showed a better cell protection effect against reactive oxygen species (ROS) compared to CS-H and hemin in vitro. Furthermore, Hep-H was selectively delivered to the injured kidney upon intravenous administration at the analysis time point (24 h) and exhibited excellent therapeutic effects on an acute kidney injury model by efficiently removing ROS, reducing inflammation, and minimizing structural and functional damage to the kidney.