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Unfortunately, many tissues, for instance the submandibular salivary glands, are toxically affected by cisplatin. Of significant interest, phytopharmaceuticals rich in flavonoids have demonstrated exceptional defense against chemotherapy induced toxicity, like chrysin (Chr); nevertheless, its low solubility and poor bioavailability have remained cornerstone issues. Accordingly, Chr was successfully encapsulated in the poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) scaffold. The developed chrysin-loaded poly(d, l-lactide-co-glycolide) nanoparticles (Chr-loaded PLGA NPs) were meticulously evaluated via comprehensive in vitro-in vivo investigations. Saliently, the outcomes of in vivo studies exhibited admirable in vivo counteraction effectiveness against cisplatin-induced toxicity in submandibular salivary glands in Albino rats upon comparing Chr-loaded PLGA NPs treated group with pure Chr as well as blank NPs treated ones. 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