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

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.