Localized Silodosin Delivery via a Separable Microneedle Patch Promoting ROS Scavenging and Modulating NA–Adra1a–Ucp2 Signaling in Dry Eye Disease

ABSTRACT Dry eye disease (DED) is a chronic ocular disorder caused by excessive reactive oxygen species (ROS) and overactivated sympathetic signaling in the lacrimal gland, which together suppress tear secretion. However, the lack of locally and sustained delivery systems limited the therapeutic translation of molecular inhibitors such as silodosin (Sd), an α1a‐adrenergic receptor (Adra1a) antagonist that can modulate the NA‐Adra1a‐Ucp2 signaling pathway and restore tear secretion. Here, we developed a separable microneedle (MN) patch to achieve localized and ROS‐responsive Sd delivery to the lacrimal gland for DED therapy. The MN patch integrates Sd‐loaded polythioketal urethane (PCTU) nanoparticles (Sd@PCTU) for controlled release and ROS scavenging, a polyvinyl alcohol/polyvinylpyrrolidone (PVA/PVP)‐based MN matrix for transdermal local delivery to the lacrimal gland, and an effervescent backing layer enabling rapid tip separation. The MN patch effectively delivers Sd, inhibits NA‐Adra1a‐Ucp2 signaling pathway, alleviates ROS‐induced inflammation, prevents myoepithelial apoptosis, and promotes tear secretion. A single administration of the MN patch restored tear production to near‐normal levels and maintained therapeutic efficacy for 28 days in DED models. This ROS‐responsive, separable MN patch offers a promising platform for localized and sustained DED therapy.