# Flavonoids Through the Nose: A New Route for Treating Sinus, Respiratory, and Brain Conditions

Flavonoids—natural plant compounds found in fruits, vegetables, teas, and herbs—are powerful anti-inflammatory and antioxidant agents, but taking them by mouth limits how well the body absorbs them. This systematic review of 40 studies (out of 225 initially identified) examined a promising alternative: delivering flavonoids through the nose. Nasal delivery could treat local sinus conditions, reach the bloodstream for body-wide effects, and even bypass the blood–brain barrier to target the central nervous system directly through the nose-to-brain pathway. The findings explain which flavonoid molecules are best suited for this route and the formulation strategies researchers are developing to overcome the nose's natural defenses.

# Flavonoids Through the Nose: A New Route for Treating Sinus, Respiratory, and Brain Conditions

## Table of Contents

- Key Points
- Why Nasal Medicine Research Matters
- What Are Flavonoids and Why Absorption Matters
- How This Systematic Review Was Conducted
- The Eight Flavonoid Families: A Plant Chemistry Guide
- Key Findings: Three Levels of Nasal Flavonoid Therapy
- Clinical Implications: What This Means for Patients
- Limitations of This Review
- Practical Takeaways for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Flavonoids are poorly absorbed orally; nasal delivery may improve absorption and reach the brain directly.
- The nasal mucosa cannot break down glycosides, so nasal therapies focus on aglycone forms like quercetin and apigenin.
- Nasal flavonoids are being researched for nasal inflammation, respiratory diseases, and brain conditions, but none are approved yet.
- This systematic review included 40 studies, many from lab or animal models, not large human trials.
- Patients should eat whole-food flavonoid sources and never attempt home nasal treatments.

## Why Nasal Medicine Research Matters

The human nose does far more than smell. It warms, humidifies, and filters the air you breathe. Its internal structure has four distinct regions, and each one offers a different opportunity for drug delivery.

The **nasal vestibule** (the front part of the nostril) acts as a deflection system, removing dust and foreign particles before they travel deeper. The **respiratory region** is the largest area of the nasal cavity and is highly vascularized (rich in blood vessels), making it excellent for absorbing medication into the bloodstream. The **olfactory region**, located high in the nose next to the olfactory bulb (the brain structure that processes smell), contains sensory neurons that lead directly into the brain. At the back of the nose, the **nasopharyngeal region** contains nasopharyngeal-associated lymphoid tissue (NALT)—an immune organ that helps block pathogens from entering the upper respiratory tract.

These anatomical features make the nose attractive for medicine. Because the nasal cavity sits so close to the brain, drugs can work locally (right in the nose), systemically (absorbed into the blood), or travel directly to the central nervous system.

Nasal delivery has several advantages over pills or injections. It is non-invasive and easy to use. It offers a rapid onset of action. The nose has lower enzymatic activity than the digestive tract and a large absorption surface. These factors mean patients may need lower doses. Most importantly, the nasal route can bypass the **blood–brain barrier (BBB)**—the protective filter that blocks many circulating compounds from entering the brain.

That barrier is a major obstacle for brain medicines. It contains active "efflux transporter" systems, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), that actively pump many drugs back out before they can reach brain tissue. The nose-to-brain pathway can sidestep this problem through three main mechanisms:

1. Transport across the **olfactory epithelium**, allowing the drug to reach the olfactory bulb and spread into the brain.
1. Absorption through the **respiratory epithelium**, followed by entry into the brain through the systemic circulation.
1. Transport along branches of the **trigeminal nerve**, which project directly into the central nervous system.

Still, the nose is not an easy route. A drug must first pass through the mucus layer, then the epithelial cell membrane, and finally the stroma and basal membrane just to work locally. For drugs meant to reach the bloodstream, there is a fourth barrier: the capillary endothelium (the thin lining of small blood vessels). Mucociliary clearance—the nose's self-cleaning mechanism that sweeps particles toward the throat—and local enzyme activity can remove or break down drugs before they are absorbed. Regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have strict requirements for nasal formulations, influencing which ingredients and delivery systems can be used.

## What Are Flavonoids and Why Absorption Matters

Flavonoids are polyphenolic compounds—natural chemicals produced by plants as secondary metabolites (substances not needed for basic growth but useful for survival). They are found in fruits, vegetables, herbs, stems, cereals, nuts, flowers, and seeds. More than **10,000 plant-derived flavonoid compounds** have been recorded in scientific literature.

These compounds are attractive for health because of their wide range of biological activities. They regulate key cellular enzyme functions and show anti-inflammatory, anticancer, anti-aging, antimutagenic (preventing genetic mutations), and antioxidant (cell-protecting) properties. Researchers have also associated them with protective effects in cardiovascular disease, atherosclerosis (hardening of the arteries), and neurodegenerative disorders such as Parkinson's and Alzheimer's disease.

The problem is how poorly the body absorbs them. Most flavonoids have low water solubility and poor absorption. When swallowed, they face rapid first-pass metabolism—a process where the liver and intestines break down much of the drug before it reaches circulation. That severely limits their therapeutic power.

However, not all flavonoids behave alike. There are two important forms:

-
**Flavonoid heterosides (glycosides)**—the sugar-bound form that dominates in plants. These are generally more water-soluble. When taken orally, they require the enzyme lactase phlorizin hydrolase (LPH) to break the sugar bond before absorption. That enzyme exists only in the small intestine's lining, and there is currently no evidence that nasal tissue can perform this same chemical reaction.
-
**Flavonoid aglycones**—the free, non-sugar form, usually present in smaller amounts in plants. Because they lack the sugar group, they are more lipophilic (fat-soluble) and can enter intestinal cells directly by passive diffusion.

This distinction matters greatly for nasal delivery. Since the nasal mucosa appears unable to break down glycosides, researchers are focusing mainly on **aglycones** for intranasal treatment—the form that can cross membranes without needing an enzyme first.

## How This Systematic Review Was Conducted

The research team followed **PRISMA guidelines** (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)—a strict, internationally recognized standard for transparently reviewing scientific literature. They searched two major databases: **Web of Science (WoS)** and **PubMed**, chosen for their strong coverage of high-impact health sciences and biomedical journals.

The search used these keyword combinations with Boolean operators:

- "flavonoid*" AND "nasal"
- "flavonoid*" AND "nose"

The asterisk (*) is a truncation symbol that captures word variations like "flavonoid" and "flavonoids." The search covered studies published in English between **December 31, 1997, and November 10, 2024**.

The search retrieved **225 total records**: 71 from Web of Science and 154 from PubMed. After removing 6 duplicates and 2 records with inaccessible full texts, **217 articles** proceeded to screening. The selection process had two phases:

1.
**Title and abstract screening** to remove studies clearly outside the scope.
1.
**Full-text review** to assess compliance with all inclusion criteria.

After full-text assessment, **177 articles were excluded**. In the end, **40 studies** met all eligibility criteria and were included in the final review.

To be included, a study had to meet **all four** of these criteria:

- Investigated the biological activities of flavonoids in relation to diseases or disorders of the nasal cavity.
- Explored the intranasal administration of flavonoids.
- Evaluated the use of cyclodextrins (ring-shaped sugar molecules used to improve drug solubility) to enhance nasal absorption of flavonoids.
- Was original research (case studies were included when relevant).

Studies were excluded if they lacked full text, were duplicates, or were reviews, editorials, letters, or unrelated to nasal delivery or flavonoid activity.

## The Eight Flavonoid Families: A Plant Chemistry Guide

All flavonoids share a basic skeleton: **15 carbon atoms arranged in three rings**—labeled A, C, and B (chemical shorthand: C6–C3–C6). They are often bound to sugars in nature as β-glucosides, which improves their water solubility, stability, and how easily the body absorbs them.

Scientists classify flavonoids into eight groups based on where the B ring attaches, how unsaturated the C ring is, and how oxidized the central ring structure is:

- Isoflavonoids
- Flavones
- Flavonols
- Flavanones
- Flavanols
- Flavanonols
- Chalcones
- Anthocyanins

The position of hydroxyl (OH) groups on rings A and B—and whether they are present on ring C—creates the many different flavonoid molecules found in nature. The review describes the chemical families most relevant to nasal therapeutics in detail. Here is what patients should know about each.

### Flavones: Powerful Enzyme Blockers Found in Herbs and Citrus

Flavones are one of the most abundant flavonoid classes. Their structure features a 4H-chromen-4-one core (a type of ring structure with an embedded oxygen atom) with a phenyl group attached at position 2. They have low water solubility and low bioavailability, which has historically limited their use as oral medicines.

Biologically, flavones are noteworthy for two actions. They act as effective **xanthine oxidase inhibitors** (blocking an enzyme that produces uric acid and free radicals), and they have strong **superoxide-scavenging capacity** (neutralizing a particularly damaging type of free radical). Synthetic prenylated flavones (flavones with an added fat-soluble prenyl group) show high potential for relaxing blood vessels, thanks to their antioxidant effects and ability to modulate nitric oxide (NO)—a molecule that widens blood vessels.

You can find flavones in:

- Celery and parsley
- Red peppers
- Chamomile, mint, and ginkgo
- Tea and oranges

Flavones generally concentrate in plant leaves and flowers. Glycosylation (sugar attachment) happens in two patterns: O-glycosylation at positions 7, 3′, and 4′, and C-glycosylation at positions 6 and 8. Examples include **apigenin, chrysin, luteolin, vitexin, isovitexin, and tangeretin**.

### Flavonols: Common Dietary Antioxidants

Flavonols—also called 3-hydroxyflavones—have hydroxyl or methoxy groups on rings A and B, plus a hydroxyl group at position C3 of the central C ring. Unlike flavones, their C-glycoside form is rare; most flavonols exist as aglycones or O-glycosides. Their wide range of biological effects is linked to their OH groups.

Flavonols protect DNA in skin cells from damage caused by ultraviolet (UV) light through hydroxyl groups at positions 5 and 7 of the A ring. They are strongly antioxidant because they bind and stabilize free radicals before those radicals can harm cells.

These molecules have high structural diversity (what researchers call "entropy") and show higher water solubility than other flavonoid subclasses. Prenylated flavonols have demonstrated potent antioxidant and vasorelaxant (blood-vessel-relaxing) activity, possibly by acting on enzymes that control nitric oxide production and by inhibiting reactive oxygen species (ROS)—unstable molecules that damage cells.

Dietary flavonols show antioxidant, antibacterial, cardioprotective, anticancer, and antiviral effects. Studies have reported preventive effects against gastric cancer risk, especially in women and smokers.

Good food sources are:

- Onions, lettuce, broccoli, and asparagus
- Tomatoes and apples
- Buckwheat leaves and sophora flowers
- Leaves of certain eucalyptus species

Well-known examples include **quercetin, galangin, kaempferol, isorhamnetin, fisetin, myricetin**, and **rutin**, which is a flavonol glycoside. Quercetin, found in onions and apples, is the most studied flavonol in human health research.

### Flavanones: Citrus Compounds With Anti-Inflammatory Power

Flavanones, also called dihydroflavones, differ from flavones by lacking a double bond between carbons C2 and C3 in the C ring. They also act as intermediates in the biosynthetic pathways that produce other flavonoids.

Flavanones show anti-inflammatory effects and moderate antioxidant capacity. In their prenylated form, they demonstrate a high ability to induce vascular relaxation (widening of blood vessels). In citrus fruits, naringin provides the characteristic bitter taste in juice and peel.

Animal research has shown that **naringenin and hesperetin** can restore altered thyroid function in rats—an early signal of benefits that might extend beyond the nose and respiratory system.

The main flavanone representatives are **naringin, naringenin, hesperidin, hesperetin, pinocembrin, and eriodictyol**, found in citrus fruits and licorice.

### Flavanols: The Tea Catechins

Flavanols—also known as catechins or flavan-3-ols—have two chiral centers (asymmetric carbon atoms that create mirror-image forms) and a hydroxyl group at position 3 of the C ring. Like flavanones, they lack the double bond between C2 and C3. But they differ in one important way: they have no ketone group (a carbon-oxygen double bond) in the C ring.

Flavanols usually appear in nature in their non-glycosylated form. They are moderately water-soluble and have very potent antioxidant effects, although they are weaker xanthine oxidase inhibitors than flavones. Because of the missing ketone group, their structure is more flexible, which limits the diversity of their chemical modifications.

Foods rich in flavanols include apples, grapes, cherries, plums, apricots, berries, bananas, pears, and blueberries. Key examples include **catechin, epicatechin, gallocatechin, epicatechin gallate, catechin gallate, and gallocatechin gallate**—the latter group being the famous tea catechins, including **epigallocatechin gallate (EGCG)**.

Daily flavanol intake may improve endothelial function (the health of blood vessel linings), protect blood vessels against damage from tobacco, and help prevent cardiovascular disease. When researchers synthesize prenylated flavanol derivatives, they see an increased ability to inhibit lipid peroxidation (a damaging process where free radicals attack fats in cell membranes), which enhances the flavonoid's blood-vessel-widening and protective effects.

### Flavanonols: The Middle-Ground Molecules

Flavanonols, or dihydroflavonols, sit chemically between flavonols and flavanones. Unlike flavanols, they possess a ketone group in the C ring. **Taxifolin** is the primary example.

Their combined hydroxyl and ketone groups create more structural variation than flavanones, but less than flavonols. Early research suggests these compounds have potent antioxidant, antibacterial, anti-inflammatory, and hepatoprotective (liver-protecting) properties.

## Key Findings: Three Levels of Nasal Flavonoid Therapy

The review organized the 40 included studies around three distinct therapeutic levels of nasal flavonoid administration. Each level has different goals, barriers, and formulation needs.

**Level 1: Effects on the nasal mucosal lining (topical action).** The first group of studies examined how flavonoids act directly on the tissues inside the nose. Delivered nasally, flavonoids can exert beneficial effects on the nasal mucosal epithelium—the protective layer of cells lining the nasal cavity. This approach is relevant for conditions such as allergic rhinitis, chronic rhinosinusitis, and nasal inflammation, where the medication needs to act quickly at the site of disease without necessarily entering the bloodstream.

**Level 2: Treatment of naso-respiratory and other systemic diseases.** The second level involves flavonoids given through the nose to treat diseases beyond the nasal cavity itself. Because the respiratory mucosa is heavily vascularized, drugs absorbed there can enter the systemic circulation rapidly—an effect historically viewed as an unwanted side effect but now seen as an opportunity. This approach is being explored for respiratory diseases and potentially for conditions elsewhere in the body that respond to flavonoids' anti-inflammatory and antioxidant actions.

**Level 3: Nose-to-brain delivery for CNS diseases.** The third and most distinctive level exploits the direct anatomical connection between the nasal cavity and the brain. By delivering flavonoid aglycones through the olfactory region or along the trigeminal nerve, researchers aim to prevent or treat central nervous system (CNS) diseases such as neurodegenerative disorders. This strategy bypasses the blood–brain barrier entirely, which could help flavonoid molecules reach brain tissue at concentrations that oral delivery cannot achieve.

## Clinical Implications: What This Means for Patients

The most direct patient takeaway is that the form of a flavonoid matters enormously. When you eat a flavonoid-rich food, your intestine must process the sugar-bound glycoside form before absorption. In nasal delivery, however, there is no evidence that the nasal mucosa can perform this chemical conversion. That means successful nasal therapies will almost certainly rely on **aglycones** (free, non-sugar forms) or on clever formulation strategies to make glycosides absorbable.

This helps explain why researchers are so interested in molecules like quercetin, apigenin, luteolin, and naringenin—these are naturally occurring aglycones that can penetrate nasal membranes more easily.

For patients with chronic sinus or respiratory conditions, topical nasal flavonoids might offer a future option with fewer systemic side effects than corticosteroids or oral antihistamines. Early research is also exploring flavonoid activity in cystic fibrosis models, where molecules such as apigenin have shown effects on the defective ion channel (the CFTR protein, specifically the common ΔF508 mutation). This could eventually support the mucus-thinning and anti-inflammatory goals of cystic fibrosis treatment.

The nose-to-brain pathway is farther from clinical reality but carries substantial long-term promise. In Parkinson's disease research, for example, intranasal flavonoid formulations are being investigated for their potential to protect dopamine-producing neurons. If successfully developed, this strategy could deliver neuroprotective doses directly to the olfactory bulb and related brain regions while avoiding the systemic side effects that limit oral brain medications.

None of these nasal flavonoid products are yet approved for routine patient use. They remain in research and development stages, with rigorous FDA and EMA oversight required before they become available.

## Limitations of This Review

This review has important limitations that patients and researchers should keep in mind. First, the inclusion criteria restricted studies to those published in English between 1997 and 2024, which could exclude relevant research published in other languages or before the search window.

Second, the search identified 225 records, but only 40 ultimately qualified for inclusion. That strict filtering, while methodologically sound, means the evidence base is still small. Many of the biological activity findings come from laboratory or animal models—such as the rat thyroid studies with naringenin and hesperetin—rather than from human clinical trials.

Third, **case studies were included only when relevant**, and reviews and editorials were excluded. This means some indirect or contextual evidence may have been missed.

Finally, the review examined studies with widely varying goals: some tested local nasal effects, others pursued systemic delivery, and still others explored nose-to-brain transport. Combining findings across these three very different objectives makes general conclusions about "nasal flavonoid therapy" necessarily cautious. The search was also conducted while some relevant formulation technologies were evolving rapidly, meaning newer delivery systems may not yet be represented in the studies captured here.

## Practical Takeaways for Patients

Until nasal flavonoid treatments reach pharmacies, patients can apply the review's insights to everyday choices.

**Prioritize whole-food flavonoid sources.** To get the widest range of flavonoid families, build meals around colorful produce:

-
**Flavonols** (quercetin, kaempferol): onions, apples, broccoli, tomatoes, tea
-
**Flavones** (apigenin, luteolin): parsley, celery, chamomile tea, red peppers, mint
-
**Flavanones** (naringenin, hesperetin): citrus fruits, especially oranges, grapefruit, and their peels
-
**Flavanols** (catechins, EGCG): green and black tea, apples, grapes, berries
-
**Flavanonols** (taxifolin): found in certain conifers and some citrus fruits

**Understand that "more" isn't necessarily "better."** Because flavonoids have low oral bioavailability, megadosing on supplements is unlikely to produce dramatic benefits. Research continues on ways to improve absorption.

**Watch for future developments in nasal formulations.** The key research questions now are formulation-based: how to keep aglycones dissolved, how to help them penetrate mucus, and how to protect them from enzymes in the nose. Cyclodextrins—ring-shaped sugar molecules that can encapsulate poorly soluble drugs—are one promising strategy the review specifically identified for enhancing nasal flavonoid absorption.

**Do not attempt to improvise nasal flavonoid treatments at home.** The studies in this review used carefully engineered formulations with specific delivery systems, doses, and safety testing. Over-the-counter nasal sprays are not formulated for this purpose, and unregulated use could damage the delicate nasal mucosa.

**For patients with chronic sinusitis, allergies, or neurodegenerative conditions:** speak with your doctor about current approved treatments. Ask whether any clinical trials of intranasal flavonoid therapies are enrolling patients in your region.

## Frequently Asked Questions

### What are flavonoids and why is giving them through the nose being studied?

Flavonoids are natural plant compounds in fruits, vegetables, teas, and herbs. They have anti-inflammatory and antioxidant properties, but when taken by mouth, the body absorbs them poorly. The nose has a rich blood supply and a direct connection to the brain, so nasal delivery might help flavonoids work locally, enter the bloodstream, or reach the brain more effectively.

### Could nasal flavonoid treatments help with brain conditions like Parkinson's or Alzheimer's disease?

The nose has a direct pathway to the brain that bypasses the blood–brain barrier. Researchers are investigating whether intranasal flavonoid aglycones can protect neurons. For example, some Parkinson's research looks at protecting dopamine-producing neurons this way. However, this is early research; no such treatment is approved yet for routine patient use.

### Are nasal flavonoid products available for patients to use today?

No. All nasal flavonoid therapies are in research and development stages. They are not approved by regulatory agencies like the FDA or EMA. Studies use carefully engineered formulations with specific delivery systems and safety testing. Do not try to improvise nasal flavonoid treatments at home, as over-the-counter nasal sprays are not designed for this and could harm delicate nasal tissue.

### Why does the chemical form of a flavonoid matter for nasal delivery?

Flavonoids exist as sugar-bound glycosides or free aglycones. The nasal mucosa appears unable to break down glycosides, so researchers focus on aglycones—like quercetin, apigenin, and luteolin—which can cross membranes directly. This is different from oral intake, where the intestine can process glycosides. This distinction is key to designing successful nasal flavonoid therapies.

### What nose or respiratory conditions might nasal flavonoids help treat?

Research suggests nasal flavonoids could act directly on nasal mucosal tissue for allergic rhinitis, chronic rhinosinusitis, and nasal inflammation. They might also enter the bloodstream to treat respiratory or systemic diseases because the respiratory mucosa is rich in blood vessels. This is still early research, but topical nasal flavonoids may offer a future option with fewer side effects than some current medications.

### What are the main limitations of the research on nasal flavonoid therapy?

This systematic review included 40 studies, mostly from laboratory or animal models, not large human clinical trials. The studies had three different goals—local, systemic, or brain delivery—so conclusions must be cautious. Also, the review only covered English-language studies up to 2024, and newer delivery technologies may not yet be represented.

### Should I take oral flavonoid supplements or eat certain foods based on this research?

The review suggests prioritizing whole-food flavonoid sources—like onions, apples, citrus, berries, tea, parsley, and celery—to get a range of flavonoid families. Because oral absorption is poor, megadosing supplements is unlikely to give dramatic benefits. If you have chronic sinus, allergy, or neurodegenerative conditions, talk to your doctor about approved treatments and possible clinical trials.

### Should I get a second opinion before trying flavonoids through the nose for chronic sinusitis?

Nasal flavonoid therapies are not yet approved for routine patient use and remain under research and development, with animal and laboratory findings forming much of the evidence. For chronic sinusitis, allergies, or neurodegenerative conditions, review current approved treatments with your doctor, and ask whether clinical trials of intranasal flavonoid therapies are enrolling. A second opinion can help confirm whether investigational options fit your situation, clarify expected risks and benefits, and prevent unproven self-treatment. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article:** "Flavonoids in Nasal Therapeutics: Biological Activities, Delivery Challenges, and Formulation Strategies—A Systematic Review"

**Authors:** Hernández JVR, Bianchi SE, Fachel FNS, Braganhol E, de Matos SP, Bassani VL.

**Affiliations:** Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul; and Programa de Pós-Graduação em Biociências, Universidade de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil

**Journal:** *Phytotherapy Research*, 2026, Volume 40, pages 4676–4709. Published by John Wiley & Sons Ltd.

**DOI:** 10.1002/ptr.70380

**Corresponding author:** Valquíria Linck Bassani (valquiria.bassani@ufrgs.br)

**Received:** July 18, 2025 | **Revised:** March 30, 2026 | **Accepted:** May 11, 2026

This patient-friendly article is based on peer-reviewed research. It is provided for educational purposes and does not constitute medical advice. Patients should consult qualified healthcare professionals about any treatment decisions.


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