Spatiotemporal bilayer microneedle patch potentiates methotrexate therapy in psoriasis by breaking the hypoxia-ROS vicious cycle.

Psoriasis is a chronic inflammatory skin disease with clear spatial stratification, featuring epidermal keratinocyte hyperproliferation and inflammatory infiltration across epidermal and dermal compartments. High oxygen consumption by keratinocytes and inflammatory cells, together with restricted oxygen diffusion caused by epidermal thickening, renders psoriatic lesions hypoxic. Hypoxia further couples with excessive reactive oxygen species (ROS), forming a vicious cycle that drives disease progression. In this study, we found that the hypoxic microenvironment was closely associated with reduced responsiveness of keratinocytes to methotrexate (MTX), a classical anti-psoriasis drug in clinic. Then, a "spatiotemporal-release" bilayer microneedle (MN) patch was developed. The patch consisted of dissolvable poly(vinylpyrrolidone) (PVP) needle tails loaded with MTX, together with phenylboronic acid-crosslinked hydrogel needle tips encapsulating MnO2 nanozymes (MnO2 NMs). After insertion into the skin of imiquimod (IMQ)-induced psoriasis-like mice, the needle tails rapidly released MTX for early epidermal intervention, whereas the hydrogel tips released MnO2 NMs in response to the high-ROS dermal microenvironment. By scavenging ROS and generating oxygen, MnO2 NMs could break the hypoxia-ROS vicious cycle, thereby improving the response of keratinocytes to MTX. In vivo experiments showed that this MN patch improved the therapeutic effect of MTX, and providing a new perspective for psoriasis treatment.