Potential of CME@ZIF‑8\nMOF Nanoformulation:\nSmart Delivery of Silymarin for Enhanced Performance and Mechanism\nin Albino Rats

Silymarin,\nan antioxidant, is locally used for kidney\nand heart\nailments. However, its limited water solubility and less oral bioavailability\nlimit its therapeutic efficiency. The present study investigated the\nenhancement of solubility and bioavailability of silymarin by loading\nit in Cordia myxa plant extract-coated\nzeolitic imidazole framework (CME@ZIF-8) against carbon tetrachloride\n(CCl<sub>4</sub>)-induced nephrotoxicity and cardiac toxicity in albino\nrats. The synthesized PEG-coated silymarin drug-loaded CME@ZIF-8 MOFs\n(PEG-Sily@CME@ZIF-8) were characterized by scanning electron microscopy,\ntransmission electron microscopy, high-resolution transmission electron\nmicroscopy, energy dispersive X-ray spectroscopy, UV–visible\nspectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy,\nthermogravimetric analysis, and zeta potential. The average crystal\nsize of CME@ZIF-8 and PEG-Sily@CME@ZIF-8 was 12.69 and 16.81 nm, respectively.\nThe silymarin drug loading percentage in PEG-Sily@CME@ZIF-8 was 33.05%\n(w/w). In the animal model with CCl<sub>4</sub> treatment, different\nparameters like serum profile, enzymatic level, genotoxicity, and\nhistopathology were assessed. Treatment with PEG-Sily@CME@ZIF-8 with\ndifferent doses of 500, 1000, and 1500 μg/kg body weight efficiently\nameliorated the alterations in the antioxidant defenses, biochemical\nparameters, and histopathological alterations and DNA damage in comparison\nto silymarin drug in a CCl<sub>4</sub>-induced toxicity rat model\nvia alleviating the cellular abnormalities and attenuation of normal\nantioxidant enzymes levels. Moreover, the molecular mechanism of drug–silymarin\ninteraction with the target protein was investigated. It involves\nthe binding pockets of silymarin molecules with VEGFR, TNF-α,\nNLRP3, AT1R, NOX1, RIPK1, Caspase-3, CHOP, and MMP-9 proteins, elucidating\nthe silymarin–protein interactions by the formation of hydrogen\nbonds and hydrophobic interactions. This study suggests that the nanodrug\nPEG-Sily@CME@ZIF-8 MOFs protect the kidneys and heart possibly by\nmitigating oxidative stress more efficiently than the conventional\ndrug silymarin.