Acid-Stable Peptide Hydrogel Delivers Insulin with pH-Triggered Intestinal Release | Research

The takeaway

G(RADA)4 self-assembling peptide hydrogel resisted gastric acid and pepsin for 14 days while enabling pH-triggered release of sulfasalazine (<5% at pH 2, 70% at pH 7.2) and insulin (<10% at pH 2, 75% at pH 7.2).

75% intestinal release
Insulin held at <10% release in stomach acid then released 75% in intestinal conditions through pH-triggered nanofiber disassembly

What the researchers found

G(RADA)4 hydrogel: 25.9 mg/L production, 70.6% recovery, 14-day acid/pepsin stability. Drug release: sulfasalazine <5% (pH 2), 70% (pH 7.2); insulin <10% (pH 2), 75% (pH 7.2) through pH-mediated nanofiber disassembly.

Why it matters

Oral delivery of peptide drugs like insulin could eliminate injections for millions. A pH-responsive hydrogel that protects drugs in the stomach and releases them in the intestine solves a key barrier.

How the study worked

Systematic screening of X(RADA)4 variants (X = G/S/A/M/Q/D/C/H), characterization by CD, TEM, cryo-SEM, rheology, stability testing in acid/pepsin, and drug release profiling at gastric and intestinal pH for sulfasalazine and insulin.

What this study cannot tell us

In vitro release studies in simulated GI fluids. In vivo bioavailability not assessed. Manufacturing scalability needs evaluation.

How to read the evidence

Thorough formulation science study with systematic variant screening. In vitro only but compelling pH-responsive release data.

When this study was published

Published in 2025.

The bigger picture

Self-assembling peptide hydrogels that respond to pH represent a breakthrough platform for oral delivery of sensitive drugs, potentially including insulin and other peptide therapeutics.

Questions still open

Would G(RADA)4-encapsulated insulin achieve meaningful oral bioavailability in animals?
Can the hydrogel protect other sensitive peptide drugs?
How does the hydrogel perform in the complex real GI environment?

Common questions

Could this enable insulin pills?

This peptide hydrogel protects insulin from stomach destruction and releases it in the intestine. It is one of the most promising approaches to oral insulin delivery, though in vivo absorption still needs to be proven.

How does pH-triggered release work?

The peptide nanofibers form a stable gel in stomach acid (pH 2) but disassemble when they reach the intestine (pH 7.2), releasing the trapped drug exactly where it needs to be absorbed.

Read the original research

Drug delivery system based on the novel acidic self-assembling peptide hydrogels: Insights into N-terminal modulation, assembly mechanism, and applications.

Colloids and surfaces. B, Biointerfaces, 261, 115451

View on PubMed ↗Publisher’s paper ↗

Citation

Guo, Yang; Deng, Yang; Huang, Wei; Song, Liang; Jia, Pengxin; Gao, Cungang; Xu, Fei; Liu, Wenshuai; Nian, Rui. (2026). Drug delivery system based on the novel acidic self-assembling peptide hydrogels: Insights into N-terminal modulation, assembly mechanism, and applications.. Colloids and surfaces. B, Biointerfaces, 261, 115451. https://doi.org/10.1016/j.colsurfb.2026.115451