“The molecular weight of a drug should be lower than 500 Da to be able to diffuse passively through the stratum corneum”. This statement has been considered as immovable dogma for a long time in pharmaceutical skin research. In certain cases, large-sized molecules can pass through the skin barrier by themselves or with some help. The DrugBiOp research lab works on micro- and nano-devices to improve drug delivery through the skin using different approaches, depending on the properties of the therapeutic agent and the treatment needs. We suggest using two different strategies to improve the passage of drugs through the skin in a minimally invasive way. The first is the use of ultra-flexible liposomes, capable of administering drugs > 1200 Da. The second, the use of microneedles to deliver lipid vesicles. As drugs to encapsulate in ultra-flexible liposomes, we have selected cyclosporine A (1.202 Da), a lipophilic immunosuppressive peptide that has serious side effects and is currently administered systemically. As a drug of similar size but greater hydrophilicity, vitamin B12 (1355 Da) was used. To study the second strategy, Vitamin B12-loaded liposomes have been used. Vitamin B12 liposomes were also included in microneedles. Both drugs can be used for the topical treatment of skin immune-inflammatory conditions. The efficacy of the lipid systems was demonstrated using an in vivo study of acute skin contact dermatitis triggered by oxazolone application on Balb/c-mice. It is expected that the new designed systems will present great advantages over current commercially available formulations, since when administered topically, the concentration of active ingredients at the site of action will increase with lower applied doses, while decreasing their systemic effects. These formulations may be extrapolated in the future to a series of both topical and systemic treatments (using the appropriate release systems, such as transdermal patches).