Oral peptide delivery has been the pharmaceutical industry's unresolved holy grail for three decades.

Peptides face multiple natural barriers: large molecular weight, protease sensitivity, and very low intestinal permeability.

In 2026, two breakthroughs overturned assumptions — Lilly's oral GLP-1 receptor agonist was approved and Duke University developed an efficient oral peptide delivery prototype — formally opening the oral peptide era.

1. High Pharmaceutical Value of Oral Peptides

Peptide drugs offer high target selectivity and low side effects, making them a hot area for innovative-drug R&D.

However, mainstream administration today is by injection.

Oral peptides are hard to deliver due to three physiological barriers.

(1) Three Physiological Barriers

1. Degradation by gastric acid and proteases

The acidic gastric environment with active proteases cuts peptides before they reach absorption sites.

2. Intestinal mucosal permeability resistance

Tight junctions between intestinal cells create a physical barrier; large, hydrophilic peptides cannot cross efficiently.

Most therapeutic peptides exceed the permeability threshold.

3. First-pass metabolic loss

The small fraction that crosses the gut wall is metabolized by the liver, with overall bioavailability typically under 1%.

(2) Unique Clinical Advantages of Oral Delivery

Improves adherence in chronic-disease patients and avoids needle phobia.

Eliminates injection-related infection risk and simplifies care.

Compresses storage and distribution costs and broadens the eligible patient population.

2. Three Technology Routes to Delivery Breakthroughs

(1) Permeation Enhancer Route

Commercialized via Novo Nordisk's SNAC technology, which uses excipients to modify local physiology, protect peptide structure, and open permeation pathways.

a. Mechanism

Locally raises gastric pH and inhibits protease activity.

Modifies membrane structure to form transient transport channels that help peptides cross the barrier.

b. Existing Limitations

Overall drug utilization is low and strict fasting is required around dosing.

Food significantly reduces efficacy, impairing daily usability.

(2) Small-Molecule Agonist Route

It abandons peptide structures and develops non-peptide small molecules, sidestepping the macromolecule delivery challenge.

Lilly's product has achieved substantive clinical results.

Pfizer's similar drug was discontinued due to hepatotoxicity, indicating persistent safety risks in this route.

Long-term benefit remains to be validated.

(3) ELP Phase-Transition Peptide Delivery

In 2026, Duke University unveiled a new delivery solution based on peptide phase-transition properties for protection and site-specific release.

a. Mechanism

Elastin-like polypeptides (ELPs) are temperature- and pH-responsive; in the stomach they coalesce into particles that encapsulate the active drug and isolate it from degradative species.

In the small intestine, they disassemble and release the active ingredient.

b. Key Highlights

Oral efficacy is essentially on par with injectable formulations, with no fasting requirement.

Can be produced at scale by fermentation, with low cost and no chemical residues.

Highly versatile platform, applicable to many peptide drugs.

c. Practical Value

Removes the need for large excipient loads, lifts fasting requirements, and breaks the prior bottleneck of oral peptide technology.

3. Global and Chinese Competitive Landscape

(1) International Oral GLP-1 Competition

(2) Status of Chinese Pipelines

Notably, the vast majority of Chinese oral GLP-1RA pipelines are non-peptide small molecules.

Truly peptide-oral platforms are rare — only ZT006 from Quality Peptide (using the QLOral oral-delivery + QLLong long-acting dual platform) is in early clinical stages.

This pattern reflects the high CMC barriers to oral peptides.

4. Industrialization Challenges for Oral Peptides

(1) High API Manufacturing Cost

Low drug utilization requires large API quantities.

Peptide synthesis capacity gaps are obvious.

Microbial fermentation and cell-free synthesis are the main directions explored for cost reduction.

(2) Multiple Contradictions in Formulation R&D

Peptide solubility varies widely with pH, requiring excipients to stabilize dissolution.

Permeation enhancers must balance efficacy with intestinal mucosal safety.

Phase-transition release models challenge traditional coating designs.

Peptide synthesis generates many impurities, requiring stringent QC standards.

(3) Stable Quality Control in Commercial Manufacturing

Manufacturing standards differ significantly between oral and injectable dosage forms.

API molecular-structure and batch consistency are key commercial-manufacturing and regulatory-inspection items.

Stable commercial-scale manufacturing capability determines market competitiveness.

5. Regulatory Review Requirements by Route

(1) Differentiated Global Standards

Permeation-enhancer products focus on new-excipient safety and drug equivalence.

Small molecules emphasize organ toxicity screening and long-term cardiovascular safety.

Novel peptide-delivery drugs have clear classification rules and need immunogenicity and degradation-product risk assessment.

(2) Domestic Review Focus

China's review of oral GLP-1 drugs for obesity is cautious.

Domestic efficacy/PK data are required, with comparison to injectables and thorough local toxicology on novel excipients.

The new regulations further standardize overseas trial data reciprocity procedures.

Closing

Oral peptide technology has completed a stage leap, with multiple launches reshaping industry structure.

New delivery technologies point to entirely new directions for the industry.

The change disrupts traditional injectable peptide pipelines while creating opportunities for high-end oral technologies.

Companies can leverage cutting-edge delivery platforms to seize market advantages and explore the integration of long-acting modification with oral delivery.

Disclaimer: This article was written by the AI research team of Nanjing Zhihe Pharmaceutical Technology Co., Ltd. for internal research reference only; not investment or medical advice.

All data sources are cited; please credit the source when quoting.

This article does not represent the official position of Nanjing Zhihe; corrections are welcome.