Octopus-inspired suction-cup microneedle patch enables intralesional SMAD7/Budesonide co-delivery to disrupt...

Gastrointestinal stenosis following endoscopic intervention remains a major clinical challenge, largely driven by excessive fibrotic remodeling rather than persistent inflammation alone. Although glucocorticoids are widely used to suppress acute inflammatory responses, their therapeutic benefit is limited since the core profibrotic circuitry governed by the TGF-β/Smad signaling pathway. In fibrotic lesions throughout the gastrointestinal tract, activated myofibroblasts and dense extracellular matrix deposition increase tissue stiffness, reinforce mechanotransduction-dependent TGF-β activation, and restrict effective intralesional drug retention, thereby establishing a self-sustaining profibrotic microenvironment. To address this mechanistic barrier, we developed an octopus-inspired suction-cup microneedle patch with a mechanically decoupled architecture composed of rigid PLGA microneedles (MN) and a flexible pectin-based substrate. This design enables efficient penetration into stiffened mucosa and stable adhesion within the moist, dynamic luminal environment. The system achieves localized co-delivery of Budesonide (BUD) and SMAD7, an endogenous intracellular antagonist of TGF-β/Smad signaling. Comprehensive in vitro mechanistic studies and in vivo wound-healing models demonstrate effective intralesional retention, significant suppression of fibrotic remodeling, and promotion of mucosal regeneration. By simultaneously targeting inflammation and the core fibrotic signaling cascade, this bioinspired microneedle platform offers a mechanistically informed and clinically translatable strategy for the prevention and treatment of post-endoscopic gastrointestinal stenosis.