Spatiotemporally engineered microneedle for microenvironment remodeling propels mucosal regeneration after tracheal mucosal injury

Remodeling the mucosal microenvironment is a pivotal step in severe tracheal mucosal injury (TMI), which may initiate a cascade of pathological events such as infection, inflammation, oxidative stress, and microvascular disruption. Current therapeutic strategies for TMI primarily focus on anti-infective or anti-inflammatory pathways, or relay on surgical interventions for complications such as stenosis. However, precise modulation of the mucosal microenvironment remains insufficient, and the unique anatomy of trachea hampers drug delivery and therapeutic concentrations maintenance. To address these challenges, a spatiotemporally engineered bilayer microneedle (MN) was developed based on silver nicotinate (AgNA) and magnesium gallate (MgGA) metal organic frameworks (MOFs) functionalized gelatin (Gel). Temporally, Gel-AgNA/MgGA MN exhibited sustained therapeutic activity through sequential degradation of Gel and MOFs. Spatially, layered loading of AgNA and MgGA MOFs enabled targeted modulation of mucosal microenvironment. Moreover, Gel-AgNA/MgGA MN efficiently penetrated mucosa and adhered firmly to tissue surface. In vitro, AgNA MOFs within MN base eradicated bacteria. MgGA MOFs within MN tips reduced ROS accumulation, promoted M2 macrophage polarization, and upregulated angiogenic genes expression. In vivo, Gel-AgNA/MgGA MN improved survival rate, restored respiratory function, and facilitated epithelium and microvascular regeneration in rabbits. This study provides insights into mucosal microenvironment remodeling and offers a potential therapeutic strategy for TMI. • This study pioneered a strategy to remodel the mucosal microenvironment for tracheal mucosal injury repair by engineering a bilayer spatiotemporal Gel-AgNA/MgGA MN. • Temporally, Gel-AgNA/MgGA MN exhibited sustained therapeutic effects through sequential degradation of Gel and MOFs. • Spatially, layered loading of AgNA and MgGA MOFs enabled targeted modulation of the mucosal microenvironment. • AgNA MOFs within Gel-AgNA/MgGA MN base eradicated intraluminal bacteria. • MgGA MOFs within Gel-AgNA/MgGA MN tips reduced submucosal ROS accumulation, promoted M2 macrophage polarization, and enhanced expression of angiogenic genes.