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Topical treatment of oral inflammatory diseases is challenging due to the intrinsic physicochemical barriers of the mucosa and the continuous flow of saliva, which dilute drugs and limit their bioavailability. Nanocarrier technology can be an innovative approach to circumvent these problems and thus improve the efficacy of topical drug delivery to the mucosa. Core-multishell (CMS) nanocarriers are putative delivery systems with high biocompatibility and the ability to adhere to and penetrate the oral mucosa. Ester-based CMS nanocarriers release the anti-inflammatory compound dexamethasone (Dx) more efficiently than a conventional cream. Mussel-inspired functionalization of a CMS nanocarrier with catechol further improves the adhesion of the nanocarrier and may enhance the efficacy of the loaded drugs. In the present study, the properties of the ester-based CMS 10-E-15-350 nanocarrier (CMS-NC) are further evaluated in comparison to the catechol-functionalized variant (CMS-C 0.08 ). While the mucoadhesion of CMS-NC is inhibited by saliva, CMS-C 0.08 exhibits better mucoadhesion in the presence of saliva. Due to the improved adhesion properties, CMS-C 0.08 loaded with dexamethasone (Dx-CMS-C 0.08 ) shows a better anti-inflammatory effect than Dx-CMS-NC when applied dynamically. These results highlight the superiority of CMS-C 0.08 over CMS-NC as an innovative drug delivery system (DDS) for the treatment of oral mucosal diseases., (© 2024 The Author(s). Macromolecular Bioscience published by Wiley‐VCH GmbH.)