Silica nanoparticles may make oral insulin possible by safely enhancing drug absorption through the intestinal wall in obese mice.
(Nanowerk Spotlight) No oral insulin formulation has ever reached pharmacy shelves. The drug that keeps hundreds of millions of people with diabetes alive still cannot be swallowed as a pill. Stomach acid destroys it. A thick mucus layer traps it. The tightly sealed cells lining the intestine refuse it entry into the bloodstream.
Injections work because they bypass these barriers entirely, delivering insulin straight into subcutaneous tissue where it absorbs directly into circulation. But that reliability carries a psychological cost that compounds over a lifetime. A person diagnosed with Type 1 diabetes at age ten and living to seventy will endure roughly 80,000 injections. Studies show that about 30% of diabetic patients feel dread around needles, and nearly half have intentionally skipped doses.
The search for an oral alternative has produced no shortage of strategies, from nanoparticle carriers to ionic liquids to chemical additives that force open the seals between intestinal cells. These additives, known as chemical permeation enhancers, have shown the most clinical traction. Two of them helped bring semaglutide to market in 2019. Semaglutide is not insulin but a smaller peptide diabetes drug that proved easier to transport across the intestinal wall.
Its success demonstrated that permeation enhancers could deliver at least some biological drugs by mouth. But existing enhancers carry significant drawbacks including irritation, nutritional interference, and a requirement to fast for 30 minutes after dosing. None has proved sufficient for a molecule as large and fragile as insulin.
Another compound called 1-phenylpiperazine (PPZ) demonstrated strong permeation-enhancing effects in laboratory studies starting in 2008, boosting transport of both small and large molecules across intestinal cell layers. PPZ activates signaling processes inside intestinal cells that cause the seals between them to open temporarily. However, it causes significant tissue damage at the concentrations needed to be effective, blocking its clinical development.
A separate research track has established that silica nanoparticles, porous spheres of silicon dioxide roughly 100 nm across, can also enhance intestinal permeability by transiently loosening the seals between cells. These particles are classified as generally recognized as safe and have cleared early-stage clinical trials.
(A) Scheme showing grafting of 1-phenyl-4-[3-(trimethoxysilyl)propyl]piperazine (“PPZ silane”) to LPSNP to generate LPSNP-1-phenylpiperazine (LPSNP-PPZ). (B) 13C NMR spectrum of PPZ silane in CDCl3 solution (75 MHz, top) and solid-state 13C NMR spectrum of the grafted material (LPSNP-PPZ, bottom). Horizontal grouping lines indicate functional-group-level assignments based on characteristic chemical-shift ranges for analogous silanes. (C) FTIR spectra of LPSNP and LPSNP-PPZ nanoparticles in the wavenumber range 1500–3100 cm−1. (D) SEM, dark field STEM, and elemental analysis of LPSNP. (E) SEM, dark field STEM, and elemental analysis of LPSNP-PPZ. Scale bar: 100 nm. (F), (G) Elemental scan of LPSNP and LPSNP-PPZ. (Image: Reproduced from DOI:10.1002/advs.202520918, CC BY) (click on image to enlarge)
The researchers synthesized a PPZ-containing molecule and bonded it onto the surface of large-pore silica nanoparticles with a dendritic, branch-like internal structure. They produced three variants with high, medium, and low densities of PPZ groups on the particle surface. Multiple analytical techniques confirmed successful grafting. The process preserved the particles’ roughly 90 nm diameter and porous architecture while altering their surface chemistry in ways expected to improve interaction with intestinal tissue.
Toxicity testing provided a stark contrast between free PPZ and its nanoparticle-bound form. Free PPZ killed roughly half of standard intestinal cells and 75% of mucus-producing intestinal cells at the same concentration. The functionalized nanoparticles showed no toxicity to either cell type at concentrations up to 2 mg/mL, even after seven days of continuous exposure. Microscopy confirmed that the cells’ internal structural proteins remained intact after nanoparticle treatment.
The team also examined how the particles interact with mucus, a barrier that traps many nanoparticle formulations before they can reach the intestinal wall. Bare silica nanoparticles swelled from about 90 to 255 nm after three hours in a mucus solution, indicating substantial binding and clumping. The PPZ-functionalized particles maintained their size near 100 nm throughout the same period, suggesting they could pass through mucus more freely.
To test whether the nanoparticles could actually move insulin across an intestinal barrier, the team grew layers of intestinal cells on permeable supports and measured how much insulin passed through over three hours. The high-density PPZ nanoparticles nearly doubled insulin transport compared to bare silica particles. A second model incorporating mucus-producing cells reinforced these results, with the PPZ-functionalized particles delivering higher insulin flux even through an intact mucus layer.
Fluorescence imaging showed that nanoparticle exposure disrupted the normally continuous protein seal at the boundaries between cells, creating a patchy, discontinuous pattern. This provided direct visual evidence that the nanoparticles enhance transport by opening gaps in the intestinal barrier. The seal fully recovered within 48 hours after nanoparticle removal, confirming that the effect was temporary and reversible.
Animal experiments began with healthy mice receiving the nanoparticles followed by an oral dose of a fluorescent tracer molecule roughly the same size as insulin. Both high-density and low-density PPZ nanoparticles significantly increased tracer absorption compared to bare silica particles or a control solution. Tissue examination revealed no signs of acute toxicity across multiple organs.
The most clinically relevant test used mice fed a high-fat diet for 12 weeks to induce a pre-diabetic state with insulin resistance and elevated blood sugar. Most oral insulin studies rely on chemically induced diabetes or healthy animals, so this model better reflects the metabolic complexity of human disease.
To protect insulin from stomach acid, the researchers encapsulated it in capsules coated with a polymer that remains intact in the acidic environment of the stomach but dissolves once it reaches the more neutral conditions of the intestine. Release tests confirmed that insulin stayed sealed inside the capsule under stomach-like acidity and released completely within one hour at intestinal pH.
Two hours after receiving nanoparticles through a feeding tube, the mice were given insulin capsules. Both PPZ nanoparticle groups showed markedly lower blood glucose than mice receiving oral insulin alone, and this reduction persisted for 8 to 10 hours. Injected insulin lowered blood glucose rapidly but the effect disappeared after about four hours. Histological analysis of the pancreas, colon, small intestine, liver, and kidney confirmed no acute toxicity.
The sustained glucose-lowering effect is notable not only for its duration but for the context in which it was achieved. These were obese, insulin-resistant animals rather than lean mice where any absorbed insulin would produce a dramatic response. The silica nanoparticles are biodegradable under physiological conditions, gradually dissolving into a naturally occurring silicon compound that the kidneys clear from the body.
Repeated-dose toxicity studies, biodistribution tracking, and immunological assessment remain necessary before clinical translation. The researchers also suggest the platform may extend to other biological drugs and to barriers beyond the intestine.
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