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Topical application of the glucocorticoid betamethasone (BM) is a common treatment for inflammatory-related skin diseases, such as psoriasis. However, enhancing its bioavailability remains challenging due to poor skin permeability. Herein, we developed and evaluated hyaluronan-cholesterol (HACH) based nanohydrogel systems (NHs) and NHs-Carbopol formulation for dermal delivery of BM. Various parameters were investigated including particle size, surface charge, encapsulation efficiency, in vitro drug release kinetics and stability. The HACH-based NHs demonstrated high encapsulation efficiency, with apparent solubility improved up to 9-fold, small size (∼190 nm) and good stability at 4 ℃ and during long-term storage. Besides, the NHs-Carbopol formulation exhibited excellent rheological properties and an occlusive effect suitable for cutaneous application. Both in-vitro (using Strat-M® membrane) and ex-vivo (using pig ear skin) permeation studies revealed that these formulations significantly improved skin permeation and drug retention in the deeper layers of the epidermis and dermis, making it advantageous for the topical delivery of BM in psoriasis treatment. Moreover, the NHs system demonstrated potential anti-psoriatic activity by downregulating the proinflammatory cytokines in vitro in human keratinocytes (HaCaT cell line) and in an ex vivo 3D skin tissue model (EpiDerm-FT™)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)