Spermidine-functionalized Janus hydrogel microneedles inhibit ferroptosis and promote healing of oral ulcers.

Abstract

Oral ulceration is a prevalent mucosal disorder, and its healing process is frequently hampered by poor local drug retention and inadequate mucosal adhesion. However, the underlying pathological mechanisms remain incompletely elucidated. In this study, transcriptomic sequencing revealed that ferroptosis serves as a key driver of oral ulcer progression. To address the limitations of conventional formulations in the wet and dynamic oral environment, we constructed an asymmetrically adhesive, ferroptosis-targeting, spermidine (SPD)-functionalized Janus hydrogel microneedle system (MN-HTSO-C). This system was fabricated via chemical grafting and dynamic Schiff base crosslinking, enabling targeted drug delivery into mucosal tissues. By specifically delivering SPD, this system effectively inhibited ferroptosis, reduced reactive oxygen species (ROS) accumulation, reprogrammed the local immune microenvironment, and thereby promoted angiogenesis and epithelial regeneration. Our work not only identifies a novel pathological mechanism but also proposes an integrated therapeutic strategy that combines targeted delivery, immunomodulation, and ferroptosis inhibition, providing a new direction for the treatment of oral ulcers and other ferroptosis-related mucosal diseases.