Peptide Nasal Spray Research: Intranasal Delivery

For decades, getting peptides into the body meant one thing: needles. Subcutaneous injections remain the gold standard for systemic peptide delivery, and for good reason — bioavailability is high, dosing is precise, and the science is well understood. But needles come with baggage. They require sterile technique, cold-chain storage, and a willingness to self-inject that not everyone shares. And for peptides that need to reach the brain, even injections fall short: the blood-brain barrier blocks most circulating molecules from entering the central nervous system.

That is why researchers have spent the last 40 years trying to make peptide nasal sprays work. The nasal cavity offers a large, highly vascularized mucosal surface that absorbs molecules directly into the bloodstream — no needles, no first-pass liver metabolism, and in some cases, a direct route to the brain that bypasses the blood-brain barrier entirely.

This article reviews the current state of intranasal peptide delivery: what works, what doesn't, and where the field is headed.

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Table of Contents

1. How Nasal Peptide Absorption Works
2. The Bioavailability Problem
3. Peptides With FDA-Approved Nasal Formulations
4. Research-Stage Intranasal Peptides
5. Bioavailability Comparison: Nasal vs. Injection
6. Technologies Improving Nasal Peptide Delivery
7. The Nose-to-Brain Pathway
8. Recent Developments (2024-2025)
9. The Bottom Line
10. References

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How Nasal Peptide Absorption Works

The inside of your nose is not the simple passageway it appears. The nasal cavity contains roughly 150 cm² of mucosal surface area, supplied by a dense network of blood vessels that sit just beneath a thin layer of epithelial cells. When a peptide solution lands on this surface, absorption can happen through two main routes.

Paracellular transport moves molecules through gaps between epithelial cells. Small, hydrophilic peptides — those under about 1,000 Daltons — squeeze through these intercellular junctions to reach the underlying blood supply. Transcellular transport carries molecules directly through cells via endocytosis or specialized channels, a process that works for some larger peptides but is generally less efficient.

Both routes face the same clock. The nasal mucosa is self-cleaning: a layer of mucus propelled by tiny cilia sweeps foreign material toward the throat, clearing most of the nasal surface every 15-20 minutes. A peptide that hasn't been absorbed by then gets swallowed and destroyed by stomach acid. This mucociliary clearance, combined with enzymatic degradation by proteases in the mucosa, is why most unenhanced intranasal peptide formulations achieve bioavailabilities below 5% compared to injection (Ozsoy et al., 2018).

Molecular weight matters enormously. Peptides up to about 6,000 Daltons have been successfully delivered across the human nasal mucosa. Above that threshold, absorption drops sharply without specialized formulation technology (Ozsoy et al., 2018).

The Bioavailability Problem

For systemic effects, nasal delivery is almost always less efficient than injection. A 2018 review in Expert Opinion on Drug Delivery found that most marketed intranasal peptide formulations achieve less than 5% bioavailability relative to subcutaneous or intramuscular routes.

That does not kill the approach — it just means formulation matters enormously. For brain-targeted delivery, the nose actually outperforms injection. But for peptides needing high systemic concentrations, the gap remains significant.

The three main barriers:

1. Mucociliary clearance — the 15-20 minute window before the dose gets swept to the throat
2. Enzymatic degradation — aminopeptidases and other proteases in the nasal mucosa break down peptides before absorption
3. Limited permeability — tight junctions between epithelial cells restrict passage of larger molecules

Each of these barriers has become a target for formulation scientists, as we'll see below.

Peptides With FDA-Approved Nasal Formulations

Despite the bioavailability challenges, several peptide and peptide-targeting nasal sprays have earned FDA approval. These products prove the concept works — when the formulation science is right.

Desmopressin (DDAVP Nasal Spray)

Desmopressin, a synthetic analog of the antidiuretic hormone vasopressin, was one of the first peptides delivered successfully via nasal spray. FDA-approved for diabetes insipidus and nocturnal enuresis, DDAVP Nasal Spray has been in clinical use since the 1980s.

The nasal bioavailability of conventional desmopressin sprays is approximately 3.4% relative to subcutaneous injection — low in absolute terms, but sufficient for clinical effect because desmopressin is extremely potent. Research has shown that spray devices produce 2-3 times higher bioavailability than nasal drops, likely because the spray distributes the dose more evenly across the absorptive surface (Harris et al., 1988).

A newer microdose formulation, AV002 (SER120), pairs desmopressin with a permeation enhancer to achieve 7.4% relative bioavailability — more than double the conventional spray — while using a fraction of the dose (Kneepkens et al., 2019).

Calcitonin-Salmon (Miacalcin)

Salmon calcitonin nasal spray won FDA approval in 1995 for postmenopausal osteoporosis, based largely on the PROOF (Prevent Recurrence of Osteoporotic Fracture) study. That trial showed 200 IU daily of nasal calcitonin reduced vertebral fracture risk by 36% over five years compared to placebo.

The nasal bioavailability of calcitonin is approximately 3% relative to injection (range: 0.3-30.6%), with wide variability between patients. Despite this low average, the 200 IU nasal dose delivers enough active peptide to produce measurable effects on bone turnover markers (Miacalcin Prescribing Information, 2017).

Calcitonin nasal spray's regulatory status has become complicated. The European Medicines Agency withdrew its recommendation for osteoporosis use in 2012, citing a small increase in malignancy risk. The FDA kept the approval but added warnings. Health Canada pulled all calcitonin nasal products in October 2013. Today, calcitonin nasal spray is considered a last-line osteoporosis treatment in the U.S.

Zavegepant (Zavzpret)

Approved in March 2023, Zavzpret is the first intranasal calcitonin gene-related peptide (CGRP) receptor antagonist for acute migraine treatment. While zavegepant is a small molecule rather than a peptide itself, it works by blocking the CGRP peptide signaling pathway, making it directly relevant to peptide-targeted nasal therapeutics.

In its Phase 3 trial, a single 10 mg nasal spray produced pain freedom in 23.6% of patients at two hours (vs. 14.9% placebo) and pain relief as early as 15 minutes post-dose. The speed of onset — patients returned to normal function within 30 minutes at significantly higher rates than placebo — demonstrates the rapid absorption possible with optimized nasal formulations (Pfizer, 2023).

Research-Stage Intranasal Peptides

Beyond approved products, dozens of peptides are being studied for nasal delivery. Here are the most notable.

Oxytocin

Intranasal oxytocin has been the subject of over 1,000 published studies, making it arguably the most-researched nasal peptide formulation. Researchers have used oxytocin nasal spray to study social cognition, autism spectrum disorder, anxiety, trust, and bonding behavior.

The systemic bioavailability of intranasal oxytocin is estimated at roughly 11% based on plasma measurements. But PET imaging data tells a different story: less than 2% absolute bioavailability reaches the brain directly via the nasal route. The gap between these numbers suggests that most absorbed oxytocin enters the peripheral bloodstream rather than traveling directly to the central nervous system (Martins et al., 2020).

A Japanese formulation called TTA-121 achieved 3.6 times higher brain concentrations than the standard Syntocinon spray in animal studies, and was used in a randomized clinical trial showing improved social interaction in young children with autism — but only at specific doses, following an inverted U-shaped dose-response curve (Munesue et al., 2022).

Intranasal Insulin

Intranasal insulin for Alzheimer's disease has produced some of the most striking results in nose-to-brain peptide research. A landmark 2025 study from Wake Forest University School of Medicine provided the first PET imaging evidence in humans that intranasally delivered insulin reaches the brain. Using a [68Ga]Ga-NOTA-insulin radiotracer, researchers confirmed significant insulin uptake in 11 brain regions associated with memory and cognition (Sai et al., 2025).

A separate 2025 clinical trial combined intranasal insulin (160 IU daily) with the diabetes drug empagliflozin in non-diabetic patients with mild cognitive impairment and early Alzheimer's. The combination improved tau tangles, cognition, neurovascular health, and immune function. Importantly, no systemic hypoglycemia occurred — a safety advantage of nasal over systemic insulin delivery (Wake Forest University, 2025).

A 2025 meta-analysis of eight controlled trials encompassing over 1,000 participants found a statistically significant odds ratio of 3.75 (95% CI: 1.49-9.40) in favor of intranasal insulin for Alzheimer's outcomes, though high heterogeneity between studies tempers the finding (PMC, 2025).

Selank and Semax

Selank and Semax are synthetic peptides developed at the Institute of Molecular Genetics in Russia, where both are approved prescription medications administered as nasal sprays.

Selank, a synthetic analog of the immunomodulatory peptide tuftsin, has been studied for anxiolytic effects. It allosterically modulates the GABAergic system while also affecting dopamine and serotonin pathways — producing effects similar to benzodiazepines in animal models but without sedation, tolerance, or abuse potential. Clinical trials in Russia confirmed its safety at doses 200-500 times the therapeutic range.

Semax, an analog of the ACTH(4-10) fragment, rapidly elevates brain-derived neurotrophic factor (BDNF) and its TrkB receptor in the hippocampus after intranasal dosing. Resting-state fMRI studies show that intranasally administered Semax modulates the default mode network structure in the human brain — direct evidence of nose-to-brain delivery producing measurable CNS effects.

Both peptides have poor oral bioavailability, making the nasal route their primary delivery method. Neither is approved outside of Russia.

Vasoactive Intestinal Peptide (VIP)

VIP, a 28-amino-acid peptide, has been studied as a nasal spray for inflammatory and neurological conditions. A 2013 mouse study demonstrated that nasal spray delivery increased brain VIP levels above what intravenous administration achieved — and that the VIP stayed in the central nervous system rather than being cleared back to the blood (PMC, 2013).

In a Phase II trial, 20 patients with active sarcoidosis received inhaled VIP (50 mcg, four times daily) for 28 days. The treatment was safe, well tolerated, and significantly reduced TNF-alpha production by pulmonary macrophages (Prasse et al., 2010). VIP has also been studied for pulmonary hypertension, where inhaled aviptadil (a VIP analog) reduced mean pulmonary artery pressure and increased cardiac output without adverse effects.

Peptide YY(3-36)

A randomized trial of 133 obese patients tested intranasal PYY(3-36), a satiety-signaling gut peptide, as a nasal spray before meals (200 or 600 mcg doses). This proof-of-concept study explored whether nasal delivery could replicate the appetite-suppressing effects of injected PYY(3-36), though results were modest (Gantz et al., 2007).

Bioavailability Comparison: Nasal vs. Injection

The following table summarizes bioavailability data from published research. "Relative bioavailability" means the percentage compared to subcutaneous or intramuscular injection of the same peptide.

Peptide	Nasal Bioavailability (Relative to Injection)	Formulation Notes
Desmopressin	~3.4% (conventional); ~7.4% (with enhancer)	AV002 uses permeation enhancers
Calcitonin-salmon	~3% (range 0.3-30.6%)	High inter-patient variability
Oxytocin	~11% (systemic); <2% (brain, PET)	TTA-121 achieves 3.6x standard brain levels
Insulin (unenhanced)	~0.4%	Plain solution, no enhancers
Insulin + chitosan powder	~17%	Tested in sheep model
Insulin + cell-penetrating peptide	~22-42%	TCTP-PTD enhancer series
Calcitonin + Intravail	>95%	Alkylsaccharide permeation enhancer
Leptin-like peptide	4x brain bioavailability vs. SC	Brain-specific measurement

Sources: Ozsoy et al., 2018; PMC, 2022; Frontiers in Pharmacology, 2022

Two patterns stand out. First, unenhanced nasal formulations consistently fall below 5% bioavailability. Second, with the right absorption-enhancing technology, some peptides can reach 20%, 40%, or even 95% of injection levels. The technology gap between "plain spray" and "optimized formulation" is often the difference between a peptide that works nasally and one that doesn't.

For a broader comparison across all delivery routes, see our guide to peptide bioavailability research.

Technologies Improving Nasal Peptide Delivery

The low baseline bioavailability of nasal peptides has spawned an entire subfield of pharmaceutical research. Here are the most promising approaches.

Absorption Enhancers

Alkylsaccharides — specifically dodecyl maltoside (DDM) and tetradecyl maltoside — are the success story of nasal permeation enhancement. These non-ionic surfactants temporarily and reversibly open tight junctions between epithelial cells, allowing larger molecules to pass through. The technology, marketed as Intravail, is already used in three FDA-approved nasal products: Tosymra (sumatriptan for migraine), Valtoco (diazepam for seizure clusters), and Opvee (nalmefene for opioid overdose).

With Intravail, peptides and proteins up to 20 kDa have achieved intranasal bioavailabilities exceeding 50% relative to injection in preclinical studies. For small peptides like calcitonin, bioavailabilities above 95% have been reported.

Cyclodextrins form inclusion complexes with peptide molecules, protecting them from enzymatic degradation while improving their ability to cross mucosal membranes. They have a long track record in nasal drug delivery research.

Chitosan, a biopolymer derived from crustacean shells, acts as both a mucoadhesive (extending contact time with the nasal surface) and a permeation enhancer (opening tight junctions via interaction with cell membrane components). Chitosan-based insulin nasal powders achieved 17% bioavailability in sheep models — a 40-fold improvement over unenhanced nasal insulin.

Cell-Penetrating Peptides (CPPs)

CPPs are short amino acid sequences that can ferry larger cargo molecules across cell membranes. Co-administration of the amphipathic CPP penetratin with intranasal insulin increased systemic absorption from 0.4% to over 22% in preclinical studies. Modified CPP variants (TCTP-PTD 13M2) pushed bioavailability to 37-42% — approaching levels that could make nasal insulin a practical clinical reality.

Nanoparticle Systems

Encapsulating peptides in nanoparticles — whether polymeric, lipid-based, or hybrid — protects against enzymatic degradation, controls release rate, and can improve contact with the nasal mucosa. Particles in the 29-39 nm range show optimal nasal deposition characteristics, with encapsulation efficiencies reaching 86-96% in recent formulations.

Thermoresponsive Hydrogels

A 2025 study tested a novel thermoresponsive polymer (PNPHO) that is liquid at room temperature but gels at body temperature. Sprayed into the nose as a liquid, it forms a gel on contact with the warm nasal mucosa, holding the peptide payload in place far longer than a conventional spray. This approach directly addresses the mucociliary clearance problem (ScienceDirect, 2025).

Dry Powder Nasal Formulations

Dry powders sidestep the stability problems that plague peptide solutions. In liquid form, peptides can degrade through hydrolysis, aggregation, and oxidation — requiring cold storage and short shelf lives. Powdered formulations remain stable at room temperature for longer periods and can incorporate mucoadhesive excipients that extend nasal residence time.

The Nose-to-Brain Pathway

For peptides targeting the central nervous system, the nose offers something no other non-invasive route can: a direct connection to the brain.

The upper portion of the nasal cavity contains the olfactory epithelium, where olfactory nerve endings project through the cribriform plate directly into the olfactory bulb. The trigeminal nerve also innervates the nasal mucosa and connects to the brainstem. Together, these two pathways allow molecules deposited in the upper nose to reach the brain without crossing the blood-brain barrier.

This is not theoretical. PET imaging in humans has confirmed that intranasally delivered insulin reaches 11 distinct brain regions. Intranasal VIP produces higher brain concentrations than intravenous VIP. And intranasal Semax produces measurable changes in brain network connectivity on fMRI.

The catch is targeting. Conventional nasal sprays deposit most of their dose in the lower nasal cavity, where the respiratory epithelium absorbs molecules into the bloodstream for systemic distribution. Reaching the olfactory region in the upper nose requires either specialized devices that direct the spray upward, or formulations that resist mucociliary clearance long enough to migrate to the olfactory area.

Precision delivery devices designed for nose-to-brain targeting — such as the Aptar CPS system used in the Wake Forest intranasal insulin trials — can improve deposition in the olfactory region compared to standard spray pumps. This distinction between respiratory and olfactory targeting is why device design matters as much as formulation chemistry for brain-directed nasal peptides.

For a comparison of nasal and injectable approaches for specific peptides, see our nasal sprays vs. injections comparison guide.

Recent Developments (2024-2025)

The nasal peptide delivery field is moving quickly. Here are the most significant recent advances.

First human proof that nasal insulin reaches the brain (2025). The Wake Forest PET imaging study confirmed direct nose-to-brain transport of insulin in humans for the first time — after decades of circumstantial evidence from behavioral studies and animal models.

Combination therapy for Alzheimer's (2025). The empagliflozin + intranasal insulin trial demonstrated that nose-to-brain peptide delivery can work alongside systemic drugs for neurodegeneration — opening a new combination therapy paradigm.

Thermoresponsive gel formulations (2025). Gel-forming nasal sprays that resist mucociliary clearance represent a new approach to the residence time problem, with 2025 data showing improved olfactory region deposition and non-toxic safety profiles.

Zavegepant long-term safety data (2025). A 52-week open-label study confirmed that Zavzpret nasal spray (up to 8 uses per month) was well tolerated, even alongside anti-CGRP monoclonal antibody therapy — validating long-term safety of peptide-targeted nasal therapeutics (PubMed, 2025).

Growing market. The global nasal drug delivery technology market was valued at $82.68 billion in 2024 and is projected to reach $168.58 billion, growing at a 7.38% compound annual growth rate. Peptide therapeutics are a significant driver of this growth.

The Bottom Line

Intranasal peptide delivery has come a long way from the early desmopressin sprays of the 1980s, but it remains a field defined by trade-offs.

For systemic delivery, nasal sprays typically achieve less than 5% of the bioavailability of injection — a gap that modern absorption enhancers, nanoparticles, and cell-penetrating peptides are steadily narrowing. The alkylsaccharide enhancer technology behind three FDA-approved nasal products has demonstrated that peptide bioavailabilities above 50% are achievable with the right formulation.

For brain delivery, the nose may actually be the best non-invasive route available. The olfactory and trigeminal nerve pathways bypass the blood-brain barrier, and 2025 human PET data has confirmed what animal studies suggested for years: intranasally delivered peptides do reach the brain. The intranasal insulin program for Alzheimer's disease is the furthest along, with combination therapy trials now showing improvements in cognition, tau pathology, and neurovascular function.

The practical reality is that nasal peptide delivery works best for a specific subset of applications: potent peptides where low absolute bioavailability is acceptable (desmopressin), CNS-targeted peptides that benefit from the nose-to-brain pathway (insulin, oxytocin, VIP, Selank, Semax), and situations where the convenience of a spray meaningfully improves patient adherence. For peptides that require high systemic concentrations, injection remains the more reliable route — though oral peptide delivery is also advancing rapidly.

The next few years will likely see new FDA approvals for nasal peptide products, driven by improved formulation technologies and a clearer understanding of the nose-to-brain pathway. For researchers and clinicians, the question is no longer whether intranasal peptide delivery works — it's which peptides, which formulations, and which patients benefit most.

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References

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11. Miacalcin (calcitonin-salmon) Nasal Spray Prescribing Information. FDA. 2017. FDA Label

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14. PMC. "Nose-to-Brain Delivery of Therapeutic Peptides as Nasal Aerosols." 2022. PMC: 9502087

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Last reviewed: February 2026. PeptideJournal.org is an independent educational resource. We do not sell peptides or supplements. This article is not medical advice — always consult a healthcare provider about treatment options.