Mechanistic benchmarking of SNAC, DDM, and LLC reveals enhancer-dependent pathways for intestinal semaglutide delivery.
Semaglutide keeps making headlines, but this time it's not about what the peptide does—it's about how to actually get it into the body through the gut. Researchers just ran a head-to-head test of three absorption enhancers: SNAC, DDM, and lauroyl-l-carnitine (LLC). The goal: find the best way to boost oral semaglutide uptake from the intestine, not just the stomach.
J Control Release
by Yuan B, Sui Y, Li H et al.
“Mechanistic benchmarking of SNAC, DDM, and LLC reveals enhancer-dependent pathways for intestinal semaglutide delivery. Yuan B(1), Sui Y(1), Li H(2), Huang J(1), Oh YC(2), Zhao Y(1), Li X(1), Sun Y(3), Dou L(4), Basit AW(5), Mai Y(6). Author information: (1)Shenzhen Oralead Pharma Ltd, Shenzhen 518107, China. (2)UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK. (3)School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China. (4)Shenzhen Oralead Pharma Ltd, Shenzhen 518107, China. Electronic address: douliu@oralead.com. (5)UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK. Electronic address: a.basit@ucl.ac.uk. (6)Shenzhen Oralead Pharma Ltd, Shenzhen 518107, China; School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen 518107, China. Electronic address: maiy6@mail.sysu.edu.cn. The oral delivery of peptide therapeutics remains constrained by poor intestinal permeability and the challenge of enhancing epithelial transport without compromising mucosal integrity. Although sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) enables gastric absorption of oral semaglutide and has also been explored for small-intestinal absorption of other peptide drugs, its suitability for enteric intestinal delivery of semaglutide remains unexplored. Here, we performed a comparative mechanistic evaluation of three permeation enhancers (SNAC, N-dodecyl-β-D-maltoside, and lauroyl-l-carnitine) for enteric delivery of semaglutide. Mechanisms were screened in epithelial monolayers and in situ intestinal absorption in rats, and the enhancers carried forward were formulated into enteric-coated capsules and evaluated in beagle dogs, with the leading candidate taken in to cynomolgus monkeys. In differentiated Caco-2 monolayers, all enhancers increased semaglutide transport but exhibited distinct transport mechanisms and barrier-response profiles. SNAC increased permeability without increasing mannitol transport or disrupting ZO-1, indicating a largely non-paracellular, cargo-dependent profile. DDM markedly increased paracellular marker transport and disrupted tight-junction organization, consistent with a primarily paracellular mode of action associated with reduced barrier recoverability. LLC showed a more favorable balance between transport enhancement and barrier recovery, while also increasing intracellular semaglutide-associated fluorescence and FD4 permeability. Rab5 immunostaining and dynasore inhibition indicated a dynamin-sensitive uptake component alongside partial tight-junction modulation. In rats, LLC produced the greatest increase in semaglutide absorption, and this effect was substantially attenuated by dynasore co-treatment. Transmission electron microscopy and tissue immunofluorescence further supported the presence of LLC-associated micelle-like structures, Rab5-related intracellular trafficking and junctional remodelling, with no overt tissue injury on local or systemic histology. For large-animal translation, citric acid and L-arginine improved semaglutide stability in intestinal fluids, and the resulting LLC-containing enteric formulation markedly increased systemic exposure in orally dosed beagle dogs and in cynomolgus monkeys following intraduodenal delivery. Collectively, these findings identify LLC as a promising permeation enhancer within the present SNAC/DDM/LLC comparison for enteric intestinal delivery of semaglutide and highlight how coordinated uptake-related and barrier-modulating mechanisms can support intestinal semaglutide absorption. Copyright © 2026. Published by Elsevier B.V. Conflict of interest statement: Declaration of competing interest Banghao Yuan, Yusheng Sui, and Liu Dou are employees of Shenzhen Oralead Pharma Co., Ltd. Yang Mai serves as a consultant to Shenzhen Oralead Pharma Co., Ltd. Banghao Yuan, Yusheng Sui, Liu Dou and Yang Mai are inventors on patent applications related to the oral peptide formulation technologies described in this work. Shenzhen Oralead Pharma Co., Ltd. has a commercial interest in the development of these technologies, including the LLC-containing enteric oral peptide formulation platform designated Macoral® for translational and commercial development. The remaining authors declare no competing interests.”
Here’s the real story. All three enhancers improved semaglutide transport across intestinal cells. But the mechanisms were very different:
SNAC increased permeability without wrecking tight junctions or raising mannitol transport. Translation: SNAC acts through a unique, cargo-dependent pathway, not just blowing open the paracellular gates.
DDM did the opposite. It ramped up paracellular marker transport and disrupted tight-junction proteins, which means it works by opening the floodgates—and the barrier takes longer to recover.
LLC struck the sweet spot. It enhanced semaglutide transport while keeping barrier recovery reasonable. It even promoted both intracellular uptake (think: cell trafficking) and mild tight-junction modulation, but without visible tissue damage.
Animal studies backed this up. LLC delivered the most semaglutide in rats, and the effect was linked to dynamin-dependent uptake (confirmed by blocking the pathway). No major tissue injuries showed up on histology, which is always a good sign for future research.
For larger animals, the team stabilized semaglutide with citric acid and L-arginine, then packed it with LLC into enteric-coated capsules. The result: much higher systemic exposure in both dogs and monkeys.
Key takeaway: LLC looks like the top contender for enteric semaglutide delivery. It combines efficient absorption with a balanced safety profile. This matters for anyone researching oral formulations of semaglutide or other peptides.
Want to explore sourcing or new formulations? Check the vendor directory for your next project.
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