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

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.