Transdermal drug delivery (TDD) is emerging route of delivery because its reduced side effects in gastrointestinal tract. However, the outermost layer of the skin (stratum corneum; SC), is recognized as the major barrier in TDD. With the recent FDA approval cases, microneedle (MN) is perceived as an effective solution. MN, however, can leave a physical damage up to the dermis, where abundant immune cells are positioning. Such damage can cause undesired immune reaction that can be fatal for children. Here, we devised a needle-free TDD based on lipid as a chemical penetration enhancer. Specifically, we designed structure of lipid nanoparticles with different fusogenicity (liposome, cubosome, and hexosome) and evaluated SC penetration performance in vitro. Our study revealed that structure engineering of lipid nanoparticle can be a fruitful approach for the needle-free TDD.