Enzymatic absorption promoters could enable oral delivery of peptide drugs like semaglutide and insulin | Research

The takeaway

Enzymatic absorption promoters (protease inhibitors, mucus-degrading enzymes, tight junction openers) could overcome GI barriers to enable oral delivery of peptide drugs, with emerging strategies showing promise for non-invasive administration.

From injection to pill
Enzymatic absorption promoters could overcome the three main barriers to oral peptide delivery: enzyme degradation, mucus, and tight epithelial junctions

What the researchers found

Three categories of enzymatic promoters: protease inhibitors (prevent degradation), mucolytic enzymes (clear mucus barrier), tight junction openers (enable paracellular transport). Applicable to oral, nasal, pulmonary peptide delivery.

Why it matters

Most peptide drugs (insulin, GLP-1 agonists, growth hormones) require injection—limiting patient compliance and access. Enabling oral delivery would transform treatment for millions of patients with diabetes, obesity, and hormonal conditions.

How the study worked

Narrative review of enzymatic strategies for improving non-invasive peptide drug absorption.

What this study cannot tell us

Review of emerging technology. Most strategies are preclinical. Safety of chronic mucosal permeability enhancement needs evaluation. Bioavailability often remains low.

How to read the evidence

Technology review of preclinical and emerging approaches. Promising but most strategies not yet clinically validated.

When this study was published

Published in 2025.

The bigger picture

The holy grail of peptide drug delivery—effective oral administration—is getting closer through enzymatic absorption technology. Combined with peptide engineering and nanoformulation, these approaches could make injectable peptides obsolete.

Questions still open

Which combination of absorption promoters achieves sufficient oral bioavailability?
Are chronic mucosal permeability changes safe long-term?
Could enzymatic promoters enable oral insulin with practical bioavailability?

Common questions

Why can't most peptide drugs be taken as pills?

Peptide drugs like insulin are proteins that get destroyed by stomach acid and digestive enzymes, blocked by intestinal mucus, and cannot cross the tight barriers between gut cells. Enzymatic absorption promoters address each of these problems to enable oral delivery.

Will we ever have truly effective oral insulin?

It is getting closer. This review catalogs new enzymatic strategies that protect peptides from digestion, clear mucus barriers, and open temporary pathways through gut walls. Combined with advances in peptide engineering, oral insulin with practical bioavailability may be achievable within the next decade.

Read the original research

Enzymatic absorption promoters for non-invasive peptide delivery.

Journal of controlled release : official journal of the Controlled Release Society, 382, 113675

View on PubMed ↗Publisher’s paper ↗

Citation

Steiger, Marilena Bohley; Steinauer, Angela; Gao, Daniel; Cerrejon, David Klein; Krupke, Hanna; Heussi, Miguel; Merkl, Padryk; Klipp, Alexander; Burger, Michael; Martin-Olmos, Cristina; Leroux, Jean-Christophe. (2025). Enzymatic absorption promoters for non-invasive peptide delivery.. Journal of controlled release : official journal of the Controlled Release Society, 382, 113675. https://doi.org/10.1016/j.jconrel.2025.113675