Noninvasive Transdermal Vaccination Using Hyaluronan Nanocarriers and Laser Adjuvant

Vaccines are commonly administered by injection using needles. Although transdermal microneedles are less invasive promising alternatives, needle‐free topical vaccination without involving physical damage to the natural skin barrier is still sought after as it can further reduce needle‐induced anxiety and is simple to administer. However, this long‐standing goal has been elusive since the intact skin is impermeable to most macromolecules. Here, we show an efficient, noninvasive transdermal vaccination by employing two key innovations: the use of hyaluronan (HA) as vaccine carriers and non‐ablative laser adjuvants. Conjugates of a model vaccine ovalbumin (OVA) and HA—HA–OVA conjugates—induced more effective maturation of dendritic cells in vitro, compared to OVA. Following topical administration in the skin, HA–OVA conjugates penetrated into the epidermis and dermis in murine and porcine skins, as revealed by intravital microscopy and fluorescence assay. Topical administration of HA‐OVA conjugates significantly elevated both humoral and mucosal antibodies, with peak levels at four weeks. An OVA challenge at week eight elicited strong immune‐recall responses. With pretreatment of the skin using non‐ablative fractional laser beams as adjuvant, strong immunization was achieved with much reduced doses of HA–OVA (1 mg kg^–1 OVA). Our results demonstrate the potential of the noninvasive patch‐type transdermal vaccination platform.