A Yeast-Based Platform for Oral Delivery of a Dual GLP-1/GIP Receptor Agonist: Engineering and Preliminary Clinical Evaluation

Key numbers

• 2.29% vs
• 6.34% vs
• 0.76% in the intervention group

Caveats

• Very small sample (n=8); treat as anecdotal.
• Preprint; not yet peer reviewed.

Oral delivery of peptides and other biologics is limited by enzymatic degradation and poor intestinal permeability. We developed a Saccharomyces cerevisiae-based platform expressing pro-DALAP, a fusion precursor of a dual GLP-1/GIP receptor agonist. The construct incorporates maltose-binding protein, a GM1-binding peptide, a cell-penetrating peptide, furin cleavage sites, and an albumin-binding domain, designed to support peptide stability, epithelial uptake, proteolytic activation, and prolonged systemic exposure. CRISPR/Cas12a-mediated integration of three expression cassettes into a protease-deficient yeast strain yielded 4.05 +/- 0.31 mg pro-DALAP/g dry biomass, compared with 1.27 +/- 0.21 mg/g in the single-copy strain, without detectable changes in cellular morphology or growth under the conditions evaluated. In vitro assays confirmed GM1 binding, furin-mediated processing, and activation of both GLP-1 and GIP receptors by DALAP. Preliminary intravenous toxicology studies in rats identified no treatment-related adverse findings at doses up to 300 micrograms/kg/day for seven days. A 12-week, open-label, randomized controlled trial evaluated enteric-coated capsules containing lyophilized yeast expressing pro-DALAP against dietary guidance alone. The baseline cohort comprised 98 generally healthy adults with overweight. An exploratory interim week-8 analysis involving eight participants per group showed numerically greater reductions in body weight (-2.29% vs. +0.14%) and waist circumference (-6.34% vs. -2.32%) in the intervention group, although neither comparison was statistically significant. These larger numerical differences were not reproduced in the completed analysis. At week 12, mean percentage changes from baseline in body weight were -0.76% in the intervention group and -0.27% in the control group; corresponding changes in waist circumference were -3.60% and -3.69%. Neither outcome showed a statistically significant between-group difference. HbA1c reduction favored the control group. Among 40 intervention-group survey respondents, 37 reported no side effects. These findings support yeast-based production and in vitro functionality of pro-DALAP and provide preliminary tolerability observations, but do not establish clinical efficacy. Validated pharmacokinetic measurements and adequately powered, blinded, placebo-controlled trials with longer follow-up are needed to determine systemic exposure and evaluate clinical efficacy and long-term safety.

K.-C. Kwon, O. Gaidarenko, N. Chang, C. Henderson

Leverage3 / 5

A method or resource many groups across the field will adopt within a year.

10% of this desk’s rubric

Magnitude3 / 5

Large gain: roughly 2x, or a clear new state of the art on a hard, unsaturated problem.

20% of this desk’s rubric

Evidence3 / 5

Solid: multiple benchmarks or cohorts, ablations, fair baselines, released code or data.

32% of this desk’s rubric

Novelty2 / 5

A new combination of known ideas.

8% of this desk’s rubric

Trajectory2 / 5

Some room to improve with obvious engineering.

5% of this desk’s rubric

Stakes2 / 5

Benefits a professional community (practitioners, clinicians, engineers).

25% of this desk’s rubric

• Citations0 (reference 20, via semantic-scholar, Oct 25, 2026, 06:17 UTC)

• Reviewed by heuristic-v10 on Oct 25, 2026, 06:17 UTC. Paper type: clinical.
• Categories: endocrinology
• BRIEF, No.5 in the Biology edition of October 26, 2026.