Vaccination is a vital healthcare strategy for preventing and controlling infectious diseases in humans and animals [1,2]. However, conventional vaccination methods have several drawbacks, such as organ damage and high maintenance costs. Oral administration can result in vaccine degradation in the gastrointestinal system, first-pass metabolism, and low and variable absorption, while injectable vaccine delivery requires skilled personnel and may require multiple doses. Additionally, vaccines need to be stored in specific conditions such as the cold chain at 4–6 °C, which complicates transportation under normal circumstances [[3], [4], [5], [6]]. Therefore, there is a need for developing innovative vaccine strategies that are low-cost and noninvasive, particularly in the context of serious threats to human health, such as the COVID-19 pandemic.

Transdermal delivery is a method of delivering drugs through the skin, which can offer a painless, non-invasive, and potentially more effective approach to immunization [7]. Transdermal vaccination has emerged as a promising alternative to traditional needle-based vaccination methods, as it can reduce the risks of unsafe injection practices and improper waste disposal, as well as the need for skilled staff and a low-temperature supply chain at the point of care [8,9]. This method targets the skin-associated professional antigen-presenting cells, which makes the skin a suitable vaccination site. The stratum corneum layer of the epidermis needs to be bypassed to reach the dermal antigen-presenting cells and induce protective immunity [8,[10], [11], [12], [13], [14]].

Enhancing the permeation of macromolecular drugs such as vaccines through the skin surface can offer a novel strategy for vaccination delivery and maintenance. Diphtheria-tetanus antigen was delivered by a transdermal patch with a hydrogel adhesive over 24 h [15]. In addition, microneedles enabled transdermal delivery of influenza vaccine through mouse skin in 2 min, inducing the necessary antibodies [16]. A microneedle-based skin patch loaded with a measles vaccine with non-human antigens was tested on animal models in 2015 [17]. Gamazo showed that the skin is a key component of the lymphatic system with great potential as a vaccine target. They examined the immunological basis of skin-associated lymphoid tissue to understand skin vaccination methods better. They contrasted conventional, chemical, or mechanical methods with the latest microneedle-based methods for delivering antigens through the skin [18].

Skin temperature elevation has been used for developing transdermal systems, especially for delivering macromolecular drugs [10,19,20]. One of the most promising transdermal drug delivery techniques is the electrothermal method, which uses a combination of heat and electrical current to enhance the delivery of vaccines through the skin [[21], [22], [23], [24], [25], [26]]. An electrothermal transdermal delivery system based on nano-engineered heating elements on polyimide substrates was developed, in which the electrical resistivity of a polyimide-patterned grid of gold nanoholes was adjusted to enable a fast-responding electrothermal skin patch, while reduced graphene oxide coating allowed drug encapsulation, such as insulin. Blood glucose control was achieved in minutes after applying insulin-loaded patches on mouse skin [22]. Although there are various methods for delivering drugs into the epidermis, transdermal vaccine delivery using an electrothermal method has not been well explored yet. Therefore, the aim of this study is to investigate tetanus-diphtheria (TD) vaccine delivery using a transdermal delivery system. By exploring the potential of the electrothermal method for transdermal vaccination, this study aims to contribute to the development of innovative and effective vaccine strategies that can address the limitations of conventional vaccination methods.