Histidine‐Engineered ZIF‐8 Nanoparticles for High‐Efficiency siRNA Delivery and Gene Therapy of Intervertebral Disc Degeneration

Abstract Ferroptosis is a major contributor to intervertebral disc degeneration (IVDD) and represents a promising therapeutic target; however, effective medications that specifically target ferroptosis are still lacking. Consequently, strategies aimed at suppressing the expression of ferroptosis‐related genes, such as small interfering RNA (siRNA) targeting activating transcription factor 3 (ATF3), appear to be a feasible therapeutic approach for IVDD. Zeolitic imidazolate framework‐8 (ZIF‐8) exhibits exceptionally high binding affinity for nucleic acids, including siRNA. Nevertheless, its practical application is hindered by challenges such as limited siRNA encapsulation and potential toxicity arising from Zn 2 ⁺ ion release during degradation. In the current study, a novel siRNA delivery system is designed with low toxicity, high encapsulation efficiency, and sustained release by hybridizing classical ZIF‐8 with histidine (H‐ZIF‐8) through defect engineering. In vitro functional studies demonstrated that H‐ZIF‐8 significantly enhances the delivery efficiency of siATF3 in nucleus pulposus cells (NPCs), and effectively suppresses ferroptosis and extracellular matrix (ECM) degradation. Furthermore, the incorporation of histidine into ZIF‐8 may improve its biocompatibility by reducing the proportion of Zn 2 ⁺ ions present. In vivo, siATF3@H‐ZIF‐8 significantly inhibited ferroptosis and alleviated intervertebral disc degeneration (IVDD) in a rat model through sustaining ATF3 knockdown. This research suggests that histidine‐modified ZIF‐8 may serve as a novel system for siRNA delivery and an effective gene therapy method for diseases, including IVDD.