Neuroregenerative Potential of <scp> <i>Astragalus microcephalus</i> </scp> ‐Derived Zinc Oxide Nanoparticles in Sciatic Nerve Injury

Peripheral nerve injuries (PNIs) are challenging to treat and call for advanced biomaterial-based approaches to support effective regeneration. This study explores the potential of a novel plant-based regenerative biomaterial, Astragalus microcephalus extract (AMEx)-functionalized zinc oxide nanoparticles (ZnO NPs) in promoting sciatic nerve repair in a rat model. ZnO NPs were synthesized via chemical and green methods, with AMEx acting as a capping and reducing agent. Comprehensive characterization (XRD, SEM, DLS, Zeta potential, UV-Vis DRS, FTIR, TGA) confirmed the structural and optical properties of the nanomaterials. The neuroregenerative potential was assessed in rats through histological and behavioral analyses, including sciatic function index (SFI), walking track analysis, and the hot plate test. A total of 35 animals were divided into five groups (n = 7 each), and treatments (5 mg/kg ZnO or AMEx/ZnO; 40 mg/kg AMEx) were administered for 1 week. AMEx/ZnO treatment significantly enhanced myelin sheath formation, reduced fibrosis and vacuolization, and improved motor coordination compared to controls. Myelin sheath thickness increased by approximately 35%-40% relative to the negative control, and muscle atrophy was reduced by ~25%-30%, indicating superior structural recovery. Behavioral assessments revealed superior functional recovery, with the AMEx/ZnO group exhibiting significantly improved SFI values from week 4 onward (p < 0.05) and the shortest pain-response latencies in the hot plate test by week 8 (~40%-50% faster than the negative control; p < 0.05). The observed therapeutic benefits were attributed to bioactive phytochemicals in AMEx, which modulated oxidative stress, inflammation, and neurotrophic signaling, facilitating structural integrity and neuroprotection. This study underscores the potential of AMEx/ZnO as an innovative regenerative biomaterial for peripheral nerve repair, leveraging the synergistic effects of phytochemicals and ZnO NPs. By integrating nanotechnology and bioactive plant compounds, AMEx/ZnO offers a biocompatible, neuroprotective, and pain-modulating approach to nerve regeneration. The significant improvements in SFI, pain latency, myelin sheath thickness, and muscle mass provide strong support for its therapeutic promise. Future studies should further elucidate its molecular mechanisms to advance clinical translation in biomaterial-based nerve regeneration therapies.