PNPHO nanocarrier for nasal semaglutide

Every approved formulation of semaglutide requires either a subcutaneous injection (Ozempic and Wegovy) or a specific oral tablet designed to survive the gut (Rybelsus, which relies on the permeation enhancer SNAC). Both routes have real-world friction. Injections require training and needles. The oral tablet must be taken on an empty stomach with water only, and the person must remain fasting for 30 minutes after. Researchers have been looking for a third path.

A paper published 30 August 2026 in the International Journal of Pharmaceutics describes one candidate: a thermoresponsive nanocarrier based on a synthetic polymer called PNPHO that encapsulates semaglutide and is designed to be sprayed into the nose^[1]. The authors, led by Sayka Khan TT and colleagues at multiple institutions, report particle sizes around 26 nm, 89% drug encapsulation, improved cell permeation in vitro, and improved glucose tolerance in animals on a 24-hour dosing schedule.

What the PNPHO nanocarrier actually is

PNPHO stands for a thermoresponsive synthetic polymer. Thermoresponsive means the material changes its physical properties at a set temperature. In this context, the formulation is liquid at lower temperatures and transitions to a more viscous gel-like state at body temperature, relevant to how it behaves once deposited on warm nasal tissue. The nanocarrier wraps semaglutide inside particles small enough to interact with nasal epithelial cells.

The study reports that the nanoparticles were monodispersed (meaning they formed a consistent, uniform size distribution) with an average diameter of 26.14 nm and a negative surface charge^[1]. Encapsulation efficiency reached 89%, meaning the nanocarrier retained roughly nine in ten semaglutide molecules during formulation. Both figures matter for a delivery system: small particle size supports cell permeation, and high encapsulation efficiency means less drug is lost in the manufacturing process.

What the experiments tested

The researchers ran three types of experiments. First, they characterized the particles physically, measuring size, charge, and encapsulation efficiency. Second, they tested permeation across nasal epithelial cell models in vitro, comparing the nanocarrier formulation to free (unencapsulated) semaglutide. Third, they moved to an in vivo animal model, looking at how long the formulation remained in the nasal cavity and what happened to glucose tolerance over 24 hours.

In the permeation experiments, the nanocarrier formulation showed greater transport across the nasal epithelial cell layer than unencapsulated semaglutide^[1]. The nasal deposition studies found preferential accumulation in the turbinates, the curved bony structures inside the nasal cavity where mucosal contact is highest. In the animal studies, the formulation showed prolonged retention in the sinus region, and the animals on a 24-hour dosing regimen showed improved glucose tolerance compared to controls.

Why nasal delivery is technically hard for a peptide like semaglutide

Semaglutide is a peptide. Its molecular weight is approximately 4,114 Da. Nasal mucosa is selective about what it absorbs: small molecules with high lipophilicity pass easily, large hydrophilic molecules like peptides do not. The nasal epithelium also contains enzymes that can break down peptide structures before they reach systemic circulation. And the mucociliary clearance system, the nose's natural cleaning mechanism, removes deposited material within minutes if the formulation does not adhere well.

These barriers explain why no peptide-based intranasal drug has yet reached the market for a systemic therapeutic effect at the scale semaglutide requires. Calcitonin nasal spray (Miacalcin) works nasally because calcitonin's therapeutic dose is very small. Semaglutide's effective dose range is meaningfully larger and its mechanism depends on systemic GLP-1 receptor engagement, not local nasal effects.

The PNPHO nanocarrier is trying to address the permeation and retention barriers simultaneously: the small particle size helps cells absorb the drug, and the thermoresponsive gel behavior extends contact time with the nasal mucosa.

Where this fits in a growing field

The PNPHO paper is not the only intranasal semaglutide research published in 2026. A paper in the Journal of Microencapsulation (August 2026, PMID 42642986) from Baldelli and colleagues used spray-dried microencapsulation with polyvinylpyrrolidone and trehalose, reporting encapsulation efficiencies above 95% and complete dissolution in nasal mucus within two hours, with over 30% of the dose absorbed in the first 20 minutes^[2]. A third paper, published earlier in 2026 in the Journal of Colloid and Interface Science (PMID 41240566), used engineered ionic liquids combining choline and salcaprozate to enhance both intranasal and sublingual semaglutide delivery, reporting hypoglycemic effects in animal models comparable to subcutaneous injection^[3].

Three independent groups publishing in 2026 on non-injectable semaglutide delivery signals genuine scientific interest. It also reflects the commercial reality: the global semaglutide market is large enough that even a marginal improvement in patient convenience would carry significant value. That incentive structure shapes which research gets funded and published.

What the research does not yet show

None of these papers are human trials. The PNPHO study's in vivo work was in animals. There is no pharmacokinetic comparison in humans showing what percentage of a nasally administered semaglutide dose reaches systemic circulation relative to a subcutaneous injection. There is no safety data in humans for sustained nasal exposure to these polymer systems. And there is no regulatory submission.

The gap between a promising animal result and a marketed drug is large for any molecule, and larger still for a complex peptide delivery system targeting a mucosal route that has historically not worked for systemic peptide administration. The history of intranasal insulin is instructive: after years of research and several trials, no product achieved regulatory approval for systemic glucose control.

The approved route for semaglutide, per the EMA's authorisation for Ozempic, remains subcutaneous injection. The oral SNAC-based tablet (Rybelsus) is the only non-injectable approved formulation. Intranasal delivery remains investigational.

What this means if you are following semaglutide

If you are a patient or clinician following GLP-1 drug development, the intranasal research stream is worth monitoring but not acting on. No intranasal semaglutide product is approved, marketed, or available through legitimate pharmacy channels in any jurisdiction we track. The research is early-stage and the animal-to-human translation question is genuinely open. For current approved options, the semaglutide overview page covers the approved formulations and their regulatory status by country.

If you are a researcher or reader interested in pharmaceutical science, the PNPHO paper adds a well-characterized nanocarrier to the field's toolkit. The 26 nm particle size, 89% encapsulation, and the 24-hour glucose tolerance data in animals are the numbers to track when comparing approaches across this literature.

What we do not yet know

The open questions: what is the bioavailability of intranasally delivered semaglutide in humans? What polymer dose is needed in a nasal spray to achieve therapeutic plasma concentrations? Are there safety signals from repeated nasal exposure to PNPHO or related thermoresponsive polymers? And what happens to the thermoresponsive properties under real-world storage conditions? The 2026 papers do not answer these questions. They do, however, set up frameworks for the next generation of experiments.