Improving oral peptide drug delivery is a longstanding pharmaceutical goal due to significant advantages in patient compliance and clinical versatility. However, despite extensive optimization of chemical permeation enhancers, orally delivered peptides such as semaglutide and octreotide remain limited by bioavailabilities below 1%, suggesting that critical determinants of gastrointestinal absorption have been inadequately addressed. In particular, mechanical forces generated by peristalsis and intimate dosage form–epithelium interactions, although influential for drug transport, have remained largely unexploited in oral drug delivery. Here we introduce a mechanobiological permeation-enhancement approach, leveraging microtopography to amplify mechanical stimuli, thus transiently modulating epithelial permeability through Piezo1 activation. Experiments employing magnetic microbeads and rose-petal-templated micropatterned films demonstrated that increased surface roughness correlates quantitatively with enhanced paracellular permeability in Caco-2 monolayers. Mechanistic studies using calcium imaging, selective inhibitors, and transcriptomics confirmed that microtopography-activated Piezo1 channels drive sustained intracellular Ca2+ influx and cytoskeletal remodeling, while finite-element modeling and ex vivo electron microscopy revealed mechanically induced transient intercellular gap formation. Importantly, integrating micropatterned films into oral enteric capsules in beagle dogs improved octreotide bioavailability by three-fold relative to the Food and Drug Administration approved formulations containing high-dose sodium caprate. These results establish microtopography-driven functional modulation of tight junctions as a safe, effective, and broadly applicable route to improve oral macromolecule absorption, offering a robust new framework to integrate physical enhancement strategies alongside traditional chemical excipients in advanced pharmaceutical formulations.
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