Cargo-aware design of dissolving microneedles: an FEA-guided rational framework reveals distinct delivery mechanisms for small and large molecules.

Authors

Yang Beibei, Dan Yang, Shen Yifeng, Tang Wenjing, Hu Wanshan, Wang Wenhao, Peng Tingting, Wu Chuanbin, Xin Pan

Published in

International journal of pharmaceutics. Pages 127394. Sep 20, 2026. Epub Sep 20, 2026.

Abstract

Transdermal delivery of glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as semaglutide (SEMA, 4113 Da) could replace weekly subcutaneous injections with patient-administered patches, thereby transforming diabetes and obesity management. Oral SEMA offers a non-injectable alternative but achieves only 0.4-1% bioavailability due to gastric degradation and limited absorption efficiency in the stomach. Dissolving microneedles (DMNs) represent an ideal transdermal platform for GLP-1RAs, however, no DMN design reported to date has achieved subcutaneous-equivalent bioavailability for a 4  kDa peptide cargo. Here, we screened a seven-mold MN library (varying needle shape, needle length and inter-needle spacing) using finite element analysis (FEA) of mechanical and skin-penetration performance. The optimal MN-T-1000-800, with the highest insertion force and most complex trapezoidal-stack needle, achieved 90.58% relative bioavailability of SEMA - the highest reported for DMN-mediated GLP-1RA delivery. To validate the generality of FEA framework, a 10-fold smaller cargo, rizatriptan benzoate (RIZ, 391 Da), was selected as model drug. The results showed that, unlike the macromolecule, the optimal geometry for the small molecule was MN-C-800-800, which exhibited a relative bioavailability of 465.40% compared with the commercial oral formulation. The two optimal geometries differed fundamentally in tip sharpness, base volume, and multi-stage profile, mechanistically rationalized by geometry-cargo matching and mechanics-dissolution coupling. We propose a cargo-aware DMN design framework that couples FEA screening with cargo-specific bioavailability validation, providing both an immediate clinical candidate for the transdermal delivery of large and small molecules and a generalizable strategy for translational DMNs development.

PMID:
42764083
Bibliographic data and abstract were imported from PubMed on 21 Sep 2026.

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