Rheumatoid arthritis (RA) is a chronic inflammatory disease whose exact etiology is yet unidentified. Dexamethasone sodium phosphate (DSP) is an established anti-inflammatory agent, but its application is limited due to its dose-dependent toxicity. This can be minimized by targeting the delivery of DSP. Zinc oxide nanoparticles (ZnONPs) have potential in the management of RA owing to their anti-inflammatory and antioxidant characteristics.The aims of this research were to develop, optimize, and determine the cytotoxicity of FA decorated DSP loaded ZnONPs.The biogenic ZnONPs have been synthesized using Piper nigrum. The Zeta potential, particle size, PDI, and loading ability of DSP-Pn@ZnONPs were improved utilizing Box-Behnken design since these factors are crucial in preserving the pharmacokinetic behavior of nanoparticles. The FA-DSP-Pn@ZnONPs were characterized via UV–visible spectrophotometer, X-ray diffraction, energy dispersive spectrophotometer, scanning electron microscopy, TEM, FT-IR, Zeta analysis and H1NMR. Nanoparticles exhibited minimal DSP release at 32.7207% at 7.4 pH (normal blood), but a substantial release of 88.72544% at 6.5 pH (RA synovial site) indicating its potential for targeting ability at the inflammatory site. Moreover, the various in vitro analyses include antioxidants, and anti-inflammatory. Furthermore, the release of FA-DSP-Pn@ZnONPs was accurately described by the Korsmeyer-Peppas model and exhibited a non-Fickian process, which was governed by both diffusion and erosion. The cytotoxicity ability and anti-inflammatory effects of NPs were determined using the MTT analysis method in non-lipopolysaccharide (LPS) and LPS-activated RAW 264.7. The FA-DSP-Pn@ZnONPs showed significant anti-inflammatory and anti-arthritis activities. At the highest concentration, it inhibited cell hemolysis and growth of the LPS-stimulated macrophage cell line, suggesting potential therapeutic interventions against RA.
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