Atopic dermatitis (AD) is a predominant and deteriorating chronic inflammation of the skin, categorized by robust burning and eczematous lacerations in diverse portions of the body. AD affects about 20% of both offspring and adults worldwide. The pathophysiology of AD combines environmental, hereditary, and immunological aspects, together with skin barrier dysfunction. The procedures used to prevent the disease are the everyday usage of creams to support the restoration of the epidermal barrier. The classical treatments include the use of topical corticosteroids as a first-line therapy, but also calcineurin inhibitors, antihistamines, antibiotics, phototherapy, and also immunosuppressant drugs in severe cases of AD. Topical drug delivery to deeper skin layers is a difficult task due to the skin anatomic barrier, which limits deeper penetration of drugs. Groundbreaking drug delivery systems, based on nanoparticles (NPs), have received much attention due to their ability to improve solubility, bioavailability, diffusion, targeting to specific types of cells, and limiting the secondary effects of the drugs employed in the treatment of AD. Even so, additional studies are still required to recognize the toxicological characteristics and long-term safety of NPs. This review discusses the current classical pharmacotherapy of AD against new nanoparticle skin delivery systems and their toxicologic risks. a prevalence of atopic conditions, as allergic rhinitis or bronchial asthma, and food allergies [2]. Topical administration of drugs is still the main therapeutic approach for AD. Despite this, several disadvantages may be cited as reduced patient compliance (a consequence of adverse effects as skin irritation or allergy), low efficiency, and specificity of these systems in delivering therapeutic drugs [3]. Innovative drug delivery systems should, therefore, exhibit the capacity to penetrate the stratum corneum (SC), which is naturally impermeable to a range of substances, in order to reduce adverse effects and increase drug targeting [3][4][5]. There is still no medication capable of reversing the pathological effects of AD. However, formulations based on nanoparticles (NPs) have been exploited for topical administration of drugs and are expected to overcome the above-mentioned limitations [6][7][8]. PathophysiologyAD, also called atopic eczema, is the most common skin disease, characterized by a pattern of pruritus, skin deterioration, and chronic inflammation [1,6,7]. This illness affects individuals in early-, mid-or late-stages of their lives and does not have a known cure so far. Over the course of the disease, the levels of IgE increase drastically leading to cutaneous signals that appear in early ages and persist until late stages of life, when they begin to disappear. Because of this, AD is also labelled as "allergic march" [2].AD results from a multiplicity of factors such as environmental injuries, impairments against the natural barrier of the skin and response of the immune system. This latter enhances the ac...