Topical calcineurin and mammalian target of rapamycin inhibitors in inflammatory dermatoses: Current challenges and nanotechnology‑based prospects (Review).

Topical therapy remains a critical component in the management of immune‑mediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroid‑free therapeutic alternatives. Despite their potential for skin‑selective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrier‑based delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential anti‑inflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hard‑to‑formulate' macromolecules in the context of psoriasis and atopic dermatitis.