1. Introduction

Dry eye disease (DED) represents a multifactorial ocular-surface disease, which is characterized by loss of tear-film homeostasis, is accompanied by ocular symptoms, tear-film instability and hyperosmolarity, ocular-surface inflammation and damage, and is etiologically ascribed to neurosensory abnormalities as a pivotal contributor¹. Current pathophysiological frameworks emphasize a self-reinforcing “vicious cycle” in which evaporative water loss produces hyperosmolar tissue damage that, directly or via inflammation, leads to loss of epithelial and goblet cells; the ensuing reduction in surface wettability promotes early tear-film break-up and further amplifies hyperosmolarity². From a neurobiological perspective, ocular-surface sensations are conveyed by trigeminal sensory pathways: cold thermoreceptors detect ocular-surface wetness and help sustain basal tear production and blinking via reflex control, while main lacrimal gland secretion is regulated predominantly by parasympathetic autonomic efferents that are reflexly driven by ocular-surface sensory input. In DED, reduced tear secretion is linked to inflammation and peripheral nerve damage, with sensitization of nociceptor endings, abnormal cold-thermoreceptor activity, and longer-term changes in trigeminal/brainstem circuits that can culminate in dysesthesias and neuropathic ocular pain³.

Dry eye disease is prevalent worldwide and is associated with substantial morbidity and socioeconomic impact. Epidemiological studies report markedly different prevalence figures because operational definitions and ascertainment methods vary across populations. Across diagnostic approaches, prevalence estimates span approximately from 5% to 50%, and sign-based estimates are generally higher and more variable than symptom-based ones⁴. A Bayesian synthesis likewise yielded an estimated overall global DED prevalence of 11.59% (about one in 11 people), whereas the estimate increased to 29.5% when analyses were restricted to studies applying TFOS DEWS II diagnostic criteria⁵. This discrepancy likely reflects primarily differences in case definition and the well-recognized discordance between symptoms and objective signs, rather than regional diagnostic practices alone, although geographic and methodological heterogeneity might contribute to residual variation^4,5. In response, TFOS DEWS II proposes a severity-stratified, stepwise management strategy that may include tear supplementation and tear-conservation approaches, interventions for lid and meibomian gland abnormalities, anti-inflammatory medications, and environmental or dietary considerations, selected according to disease features and severity⁶. The report also emphasizes that many commonly used interventions still lack robust Level 1 support—often because studies are limited by inadequate masking, randomization, or controls, and sometimes by selection bias or small sample sizes, so predicting the relative benefit of specific options (including across aqueous-deficient and evaporative subtypes) remains challenging⁶. Together with the frequent mismatch between symptoms and objective signs⁴, these limitations sustain interest in therapies that move beyond tear replacement alone, including approaches designed to enhance tear production⁶.

Intranasal pharmacological neuroactivation of the nasolacrimal reflex (NLR), also referred to as the trigeminal–parasympathetic pathway, has been proposed as a novel approach to increase endogenous tear production in DED⁷. This therapeutic concept is consistent with established lacrimal physiology: secretion from the main lacrimal gland is regulated predominantly by autonomic parasympathetic nerves, and the activity of these efferent pathways is governed by reflex mechanisms initiated by sensory afferents supplying the ocular surface, with downstream engagement of brainstem regions involved in lacrimation control³. The most developed clinical example is varenicline solution nasal spray (OC-01; Tyrvaya™), an intranasal, water-soluble small-molecule nicotinic acetylcholine receptor agonist approved in the USA for the treatment of DED⁷. In pivotal trials (ONSET-1 and ONSET-2), twice-daily administration produced rapid, statistically significant, clinically meaningful improvements in DED signs and symptoms over a period of 4 weeks, with efficacy maintained through 12 weeks in the MYSTIC study; the most common adverse events were mild, transient sneezing and cough, consistent with the nasal route of delivery⁷. In the randomized, double-masked, vehicle-controlled ONSET-1 (phase 2b) and ONSET-2 (phase 3) trials, OC-01 (varenicline solution) nasal spray produced statistically significant increases in anesthetized Schirmer test scores vs. vehicle at 4 weeks (including a higher proportion of patients attaining ≥10 mm STS improvement in ONSET-2). Symptom outcomes based on the eye dryness score also improved vs. vehicle, with significance depending on dose and assessment setting (clinic vs. controlled adverse environment). These trial results were part of the evidence base reviewed in NDA 213978 and supported U.S. approval of varenicline solution nasal spray for the treatment of the signs and symptoms of dry eye disease^8-10. A systematic review and meta-analysis of three randomized controlled trials found a statistically significant improvement in anesthetized Schirmer test score (tear production) at day 28 with varenicline nasal spray vs. placebo/vehicle, with no significant differences in serious adverse events or ocular adverse events, but a higher incidence of nasal cavity–related adverse events—particularly cough and throat irritation¹¹. Consistent with this, a post-hoc pooled analysis of the ONSET-1, ONSET-2 and MYSTIC programs reported high treatment completion (93.5% overall), while ocular treatment-emergent adverse events were comparable to those of vehicle in terms of frequency and severity, with the most commonly reported ocular events (e.g., reduced visual acuity and conjunctival hyperemia) each occurring in the ~3–4% range; most adverse events were non-ocular and related to the nasal route of administration (with sneezing being most frequently reported and predominantly mild)¹².

The main neural pathways targeted by intranasal neuroactivation/neurostimulation—trigeminal afferents and the olfactory route—and their relevance to tear stimulation and central nervous system (CNS) access are summarized in Figure 1.

Figure 1. Schematic overview of intranasal (IN) delivery/neurostimulation pathways relevant to dry eye disease and central nervous system (CNS) targeting.

Intranasal stimulation/spray engages trigeminal afferents within the nasal cavity (via the trigeminal ganglion and ophthalmic branch) and the olfactory route (olfactory bulb), supporting reflex neuromodulation and potential nose-to-brain transport. Created by the authors using adapted images from Servier Medical Art, licensed under CC BY 4.0.

Alongside pharmacological approaches, device-based intranasal electrical neurostimulation has been explored as a non-pharmacological way to activate the nasolacrimal reflex/pathway and augment endogenous tear secretion. In a prospective, single-arm, non-randomized open-label pilot study in 40 patients with mild-to-severe DED, Schirmer testing demonstrated a higher tear production during stimulation than without stimulation at every visit through day 180, while symptom measures improved and conjunctival staining decreased over time; no serious device-related adverse events were reported¹³. Two subsequent pivotal studies with an intranasal tear neurostimulator further quantified tear responses: a randomized, double-masked, dual-controlled 1-day crossover trial found Schirmer scores significantly higher during active intranasal stimulation than during active extra nasal or sham intranasal control applications, and a 180-day open-label cohort showed that stimulated Schirmer scores remained significantly greater than unstimulated values at day 180; across both studies, no serious device-related adverse events were observed¹⁴. In line with these findings, a meta-analysis pooling 17 clinical trials (901 participants) reported a significant increase in Schirmer II scores after intranasal tear neurostimulation, with reported adverse events described as mild-to-moderate and no serious adverse events, while also noting substantial between-study heterogeneity and unresolved differences in study methods and stimulation parameters—supporting the need for more standardized designs and endpoints¹⁵.

Beyond tear stimulation, intranasal administration is being explored as a non-invasive delivery strategy to increase drug exposure within the central nervous system by bypassing the blood–brain barrier. Current models describe direct nose-to-brain transport primarily via olfactory and trigeminal nerve–associated routes, potentially involving both intracellular axonal transport and extracellular movement along perineural/perivascular or Cerebrospinal Fluid (CSF)- connected spaces, although the exact contribution of each mechanism remains incompletely defined. Practical performance is limited by nasal anatomy and physiology, including rapid mucociliary clearance that shortens residence time, the relatively small proportion of olfactory mucosa in humans compared with common preclinical species, and strong dependence on formulation and delivery factors (e.g., viscosity/gelation, device-dependent deposition), as well as inter-individual variability in nasal geometry and administration technique^16,17. Notably, pharmacokinetic findings summarized in these reviews report that, after intranasal dosing in preclinical models, drug exposure can be detected in structures such as the olfactory bulb and trigeminal regions and—in some studies—also in the optic nerve, suggesting that the same nasal neural corridors may extend drug exposure beyond the brain to include peri-ocular neural tissues¹⁶.

Preclinical studies support intranasal delivery as a non-invasive route to target the eye and optic nerve with a complex amnion-derived biological secretome (ST266), the proteinaceous secretome of amnion-derived multipotent progenitor (AMP) cells^18-20. In rodent biodistribution experiments, radio-labeled intranasal ST266 reached ocular tissues and was detected in the vitreous and optic nerve within 30 minutes of administration. In the MOG-induced experimental autoimmune encephalomyelitis (EAE) model of optic neuritis, once-daily intranasal ST266—initiated either before optic neuritis onset or after disease onset—attenuated optokinetic response (OKR) impairment and was associated with reduced retinal ganglion cell (RGC) loss and axonal injury, together with decreased optic nerve inflammatory infiltration and mitigated demyelination compared with placebo-treated EAE mice¹⁸. Building on this, studies comparing post-onset regimens found that continuous intranasal ST266 treatment (once or twice daily) from Day 15 through Day 56 preserved OKR performance, improved RGC survival, and reduced optic nerve inflammation and demyelination, whereas limiting treatment to Days 15–30 and then discontinuing it primarily delayed functional decline and showed limited long-term benefit on RGC survival and optic nerve pathology at Day 56¹⁹. In a traumatic optic neuropathy paradigm using optic nerve crush, intranasal ST266 started immediately after injury attenuated early OKR decreases and reduced optic nerve axonal and myelin damage; effects on visual function and RGC survival were more limited after more severe crush injury and at later post-injury time points²⁰. Collectively, these findings provide a preclinical rationale to further investigate intranasal delivery as a strategy to deliver protein therapies to the retina and optic nerve in models of inflammatory and traumatic optic neuropathy^18-20.

In this narrative review, we synthesized clinical evidence for intranasal tear stimulation in DED—including pharmacological (varenicline) and device-based neurostimulation—alongside mechanism- and translation-related literature on intranasal delivery to neural targets. We focus on what is currently supported, what remains uncertain (particularly regarding ocular pharmacokinetics and tissue exposure), and what studies are needed to establish intranasal delivery as a credible platform for ocular neuroprotection.

2. Methodology

The review was conducted by performing a literature search in the main biomedical databases (PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library) and in ClinicalTrials.gov to identify complete and ongoing studies. The last search was performed on 5 January 2026 and used combinations of keywords related to the intranasal route and nasal formulations (“intranasal”, “nasal spray”, “nose-to-brain”, “nose-to-eye”), dry eye disease and tear secretion outcomes (“dry eye disease”, “tear production”, “Schirmer test”, “ocular surface staining”, “symptoms”), trigeminal/nasolacrimal reflex activation and neuromodulation (“trigeminal”, “nasolacrimal reflex”, “tear neurostimulation”, “intranasal electrical stimulation”, “parasympathetic”), and ocular neuroprotection targets and models (“retina”, “optic nerve”, “retinal ganglion cell”, “optic neuritis”, “traumatic optic neuropathy”, “neuroprotection”), including agent- and platform-specific terms whenever relevant (e.g., “varenicline”, “OC-01”, “TYRVAYA”, “ST266”, “erythropoietin”, “resveratrol”, “nanoparticles”, “liposomes”). Only articles published in English were considered. The reference lists of included papers and relevant reviews were also screened to identify additional eligible studies not captured by the initial search.

Whenever full-text articles were available, they were reviewed in detail and the relevant data were incorporated into the development of this narrative review. We gave priority to randomized and vehicle-controlled clinical trials, as well as post-approval evidence syntheses, addressing pharmacological intranasal neuroactivation for dry eye disease, with particular attention paid to tear production outcomes such as the Schirmer test, patient-reported symptom measures, ocular surface staining when available, and safety and tolerability findings. We also considered clinical studies and meta-analyses focused on device-based intranasal tear neurostimulation.

To explore the potential role of intranasal delivery beyond tear stimulation alone, we additionally included mechanistic and translational studies examining olfactory and trigeminal transport routes, as well as the practical constraints imposed by nasal deposition and mucosal clearance. Preclinical studies were included only when they investigated intranasal administration in retinal, optic nerve, or closely related neuro-ophthalmic models and reported at least one outcome of direct translational relevance, namely ocular or optic nerve tissue exposure, functional outcomes involving the visual pathway, and/or structural markers of neuroprotection. On this basis, agents such as ST266, erythropoietin, and resveratrol nanoparticles were retained as proof-of-concept examples, not as a comprehensive list of intranasal candidates, but because they fulfilled these criteria and were directly relevant to the ocular and optic nerve translational perspective of this review.

Given the marked heterogeneity across study designs, patient populations, interventions, and outcome measures, the available evidence was synthesized qualitatively rather than pooled in a new meta-analysis.

Since this manuscript is a literature-based narrative review and did not involve new patient recruitment, prospective interventions, or the analysis of identifiable personal data, formal ethics committee approval was not required. No new clinical cases were collected for the purposes of this review, and any mention of consent pertains only to the original studies included in the literature and their respective ethical frameworks. A PRISMA-informed flow diagram was constructed to transparently summarize the study selection process within this narrative review (Figure 2).

Figure 2: PRISMA-informed flow diagram illustrating the study selection process for this narrative review.

3. Results

3.1. Pharmacological intranasal neuroactivation for dry eye disease: varenicline solution nasal spray (OC-01)

Randomized, double-masked, vehicle-controlled trials have evaluated OC-01 (varenicline solution) nasal spray, a selective nicotinic acetylcholine receptor agonist developed to pharmacologically activate the trigeminal parasympathetic pathway via the nasal mucosa, thereby stimulating natural tear production^8,9. In the phase 2b ONSET-1 study, twice-daily OC-01 at 0.03 mg and 0.06 mg produced statistically significant improvements in basal tear production versus vehicle at day 28, measured by anesthetized Schirmer test score (least-squares mean differences vs. vehicle: 7.7 mm and 7.5 mm; both p < 0.001)⁸. Consistently, the phase 3 ONSET-2 trial reported a significantly higher proportion of patients achieving a ≥10 mm Schirmer improvement at week 4 with OC-01 0.03 mg and 0.06 mg compared with vehicle (47.3% and 49.2% vs. 27.8%; p < 0.0001 for both), alongside a greater mean Schirmer change from baseline vs. vehicle⁹. Key characteristics and outcomes of the ONSET program are summarized in Table 1.

Post-approval syntheses have helped frame the efficacy and safety signals observed in the pivotal trials. A PRISMA-guided systematic review of randomized studies and post hoc RCT (Randomized Controlled Trial) analyses comparing bilateral OC-01 varenicline nasal spray with vehicle (publications December 2021–September 2023) included eight studies and found inter-group effects favoring OC-01 for key outcomes, including an anesthetized Schirmer test mean difference of 6.6 ± 2.3 mm and an Eye Dryness Score – Visual Analog Scale or EDS-VAS mean difference of −7.5 ± 2.2 points; a smaller but favorable difference was also reported for total corneal fluorescein staining (−1.2 ± 0.01 points). The authors noted similar patterns with the 0.03 mg and 0.06 mg doses and reported overall adherence >93%, while also emphasizing interpretive constraints such as study heterogeneity, short follow-up, and the need to contextualize symptom changes²¹. In parallel, a pooled post hoc safety/adherence analysis across ONSET-1, ONSET-2, and MYSTIC (n = 1061 randomized) reported that 93.5% of participants receiving varenicline solution nasal spray completed the treatment period; the most frequent treatment-emergent adverse event was predominantly mild sneezing, with other common non-ocular events including cough, throat irritation, and nasal (instillation-site) irritation, and no drug-related serious adverse events were identified¹². Finally, an FDA Adverse Event Reporting System or FAERS-based pharmacovigilance study (inception–April 2024; 1125 reports linked to varenicline solution) did not detect disproportionate reporting of specific ocular adverse events vs. nasal saline, but—using systane as the comparator—identified higher reporting odds for lacrimation (ROR 2.18, 95% CI 1.46–3.26), visual impairment (ROR 2.27, 95% CI 1.24–4.16), and photophobia (ROR 7.50, 95% CI 3.68–15.27), which the authors presented as signal-detection findings that do not establish causality and require cautious interpretation alongside controlled trial evidence²².

3.2. Device-based intranasal tear neurostimulation in dry eye disease

Clinical evidence indicates that intranasal tear neurostimulation can acutely increase lacrimal output in dry eye disease by electrically activating trigeminal afferents within the nasal cavity and engaging the nasolacrimal pathway. In a prospective, single-arm, open-label pilot study (n=40; mild-to-severe DED), stimulated Schirmer scores (with anesthesia) were consistently higher than unstimulated values at every visit through Day 180, with parallel reductions from baseline in patient-reported symptom measures (VAS categories and OSDI) and improvements in ocular surface staining over follow-up; no serious device-related adverse events were observed¹³.

Two pivotal studies further quantified tear responses under control conditions and with longer exposure to daily use. In a randomized, double-masked, dual-controlled 1-day crossover trial (n=48), active intranasal stimulation produced markedly higher Schirmer scores than both an active extra nasal control and a sham intranasal condition (25.3 ± 1.5 mm vs. 9.5 ± 1.2 mm and 9.2 ± 1.1 mm; p < 0.0001), supporting a robust acute tearing effect. In a separate 180-day single-arm, open-label cohort (n=97 enrolled; n=89 completing Day 180), stimulated tear production remained significantly greater than unstimulated tear production at day 180 (17.3 ± 1.3 mm vs. 7.9 ± 0.7 mm; p < 0.0001), with significant symptom improvements reported at earlier follow-ups (Days 7 and 30) and most participants describing symptoms as better or somewhat better at day 180; across both studies, no serious device-related adverse events were reported¹⁴.

A meta-analysis synthesizing published trials up to October 2022 (15 studies; 17 clinical trials; 901 patients) found that intranasal tear neurostimulation was associated with higher post-stimulation Schirmer II values (pooled mean difference 14.12 mm, 95% CI 8.93–19.31; p < 0.001), while also documenting substantial between-study heterogeneity (I²=95%) and emphasizing ongoing uncertainty around optimal stimulation parameters and standardization of outcome assessment; reported adverse events were mild to moderate, with no serious events described¹⁵. Mechanistic and translational overviews frame intranasal neurostimulation as a neuromodulator strategy aimed at restoring lacrimal functional unit responsiveness via the nasolacrimal reflex and potentially influencing additional tear film components (e.g., goblet cell and meibomian gland-related secretion), while also noting that neural pathways and modulatory mechanisms remain incompletely defined²³.

3.3. Intranasal delivery as a platform for ocular/optic nerve neuroprotection: preclinical and translational evidence

Preclinical data indicate that intranasal administration can deliver biologically active protein therapeutics to ocular and optic nerve tissues in rodents. After intranasal dosing in rats, radio-labeled ST266 (an Amnion-derived Multipotent Progenitor or AMP cell–derived secretome) was detected in the vitreous and optic nerve within 30 minutes, with higher concentrations in these tissues than across the brain, consistent with rapid access of secretome proteins to the visual pathway. In Experimental Autoimmune Encephalomyelitis or EAE-associated optic neuritis, daily intranasal ST266 preserved visual function (OKR) and reduced RGC and axonal loss against placebo, alongside lower optic nerve inflammatory infiltration and demyelination. When started after peak onset (e.g., Day 15 post-immunization), ST266 halted or reversed early OKR decline after treatment initiation and was associated with improved RGC/axon outcomes, with stronger effects when initiated earlier in the course¹⁸. A regimen-focused study showed that continuous intranasal ST266 (once or twice daily) from onset through day 56 significantly improved OKR, reduced RGC loss, and decreased optic nerve inflammation/demyelination vs. multiple placebo controls (including saline and albumin controls), while a 15-day course (Days 15–30) mainly delayed OKR decline with limited long-term structural benefit at Day 56. Once-daily continuous dosing performed similarly to twice-daily dosing, and comparisons supported that benefits were attributable to the specific ST266 secretome rather than non-specific protein load or collection medium¹⁹. Evidence also extends to trauma: in mouse optic nerve crush, intranasal ST266 begun immediately after injury attenuated early OKR decline after a 1-second crush and reduced axonal and myelin damage, with trends toward greater RGC preservation; effects were more limited after a more severe (4-second) crush, where RGC survival improved but OKR remained profoundly reduced [20]. Overall, these studies support intranasal delivery as a non-invasive route with functional and histological benefits in rodent inflammatory and traumatic optic neuropathy models, while explicitly leaving human ocular/optic nerve accumulation and mechanisms as translational uncertainties^18-20.

More broadly, intranasal administration leverages the olfactory and trigeminal pathways as a rapid, noninvasive interface to cranial targets, spanning established nasal–ocular reflex circuitry (e.g., trigeminally mediated lacrimal functional unit activation) and emerging nose-to-brain delivery strategies, while remaining constrained by formulation, safety/toxicology, and species-to-human translational factors^24-26. Overall, the nose-to-brain literature indicates that intranasal delivery is most likely to succeed when formulations/devices achieve deposition in the upper nasal cavity/olfactory epithelium—where CNS access via olfactory and trigeminal connections is proposed but remains debated in humans—and Computational Fluid Dynamics or CFD syntheses suggest that olfactory deposition is driven primarily by particle inertia/size (smaller, low-impaction particles) rather than by breathing flow rate alone^27-28.

Composition–fractionation experiments indicate that ST266’s full secretome profile contributes to its neuroprotective efficacy in EAE-associated optic neuritis. When proteins >50 kDa were removed, the resulting <50 kDa fraction retained a significant demyelination-attenuating effect in optic nerve tissue but showed only non-significant trends toward preserving retinal ganglion cell (RGC) survival and visual function, and it was less potent than unfractionated ST266 in a Schwann-cell proliferation assay. Overall, these findings support a multi-component mechanism in which higher-molecular-weight constituents help sustain the optimal neuroprotective profile rather than a single dominant mediator²⁹.

Beyond ST266, other intranasal approaches have been tested to reach posterior-segment targets non-invasively. In an N-methyl-N-nitrosourea or MNU-induced murine model of retinal degeneration, intranasal erythropoietin (EPO) produced significantly higher retinal EPO levels than intravenous dosing, with concomitant structural and functional benefits: better preservation of retinal architecture (including Outer Nuclear Layer or ONL thickness), improved Electroretinography or ERG responses and optokinetic performance, reduced photoreceptor apoptosis, and changes consistent with a more favorable oxidative-stress profile. Compared with intravenous delivery, intranasal EPO yielded lower circulating EPO levels and a smaller increase in hematocrit, while still showing protective efficacy in the retina³⁰. In an EAE model of optic neuritis, daily intranasal resveratrol nanoparticles (RNs) at 8.44 mg/kg significantly improved RGC survival vs. an equivalent empty-nanoparticle vehicle, whereas lower-dose RNs and the same-dose unconjugated resveratrol showed non-significant neuroprotective trends. Notably, the RGC benefit with intranasal RNs occurred without significant reductions in optic nerve or spinal cord inflammation/demyelination and without significant improvement in OKR-based visual function or EAE clinical scores³¹.

Taken together, these studies justify further investigation of intranasal delivery for ocular/optic-nerve neuroprotection, while highlighting a key translational gap: robust, standardized pharmacokinetic and tissue-exposure validation in ocular/optic-nerve compartments across agents and formulations^29-31.

Preclinical models and key outcomes are summarized in Table 2.

3.4. Cross-cutting constraints and formulation/engineering considerations

Across indications, intranasal delivery is constrained by nasal anatomy and physiology—including limited residence time, mucociliary clearance, and local enzymatic activity—and by formulation/device attributes that shape droplet/particle behaviors and, ultimately, deposition and absorption. Keller et al. outline how these biological constraints intersect with formulation choices, device performance, and the need for careful local/systemic safety and toxicological assessment during development²⁵. In nose-to-brain applications, Agosti et al. described lipid-based nanocarriers (e.g., Solid Lipid Nanoparticles or SLNs and Nanostructured Lipid Carriers or NLCs) as platforms intended to enhance drug stability, protect susceptible compounds from degradation, and tune release profiles, while emphasizing that challenges such as nanoparticle toxicity and optimization of administration strategies remain relevant for translation²⁶. Consistently, a CFD systematic review and meta-analysis reported wide variability in simulated olfactory-region deposition and identified particle-related determinants as the most robust predictors: smaller particle size and lower impaction parameter correlate with higher olfactory deposition, whereas breathing flow rate shows no consistent association, mirroring substantial heterogeneity across models, anatomical definitions, and device approaches²⁷. Collectively, these findings indicate that efficient, reproducible targeting of the olfactory region cannot be assumed and requires integrated consideration of anatomy, formulation, device design, and safety to support clinical translation^25-27.

4. Discussion

4.1. Where intranasal “tear restoration” fits in contemporary DED care

Dry eye disease (DED) is now commonly conceptualized as a multifactorial ocular-surface condition in which disrupted tear-film homeostasis is the central concept and is accompanied by ocular symptoms. Within this framework, tear-film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are treated as key etiological contributors. Mechanistically, evaporative water loss and the resulting hyperosmolar stress can initiate and sustain a self-perpetuating cycle that promotes epithelial and goblet cell loss, reduced surface wettability, earlier tear-film breakup, and symptom generation spanning ocular pain/dryness sensations and visual disturbance. Epidemiological evidence also aligns with this model, showing that signs are often more prevalent (and more variable) than symptoms, and Bayesian prevalence estimates similarly indicate a markedly higher frequency of objective signs than symptomatic disease, consistent with the recognized symptom–sign discordance. Current management is therefore presented as a staged, severity-based approach aimed at restoring tear-film homeostasis while accounting for overlapping aqueous-deficient and evaporative drivers^1-6. In this context, intranasal approaches that pharmacologically activate the nasolacrimal reflex (trigeminal parasympathetic pathway) aim to increase endogenous tear production by leveraging reflex circuits in which ocular-surface sensory input can drive predominantly parasympathetic control of lacrimal gland secretion. By shifting the therapeutic action away from direct ocular instillation, this strategy may offer practical advantages over conventional ophthalmic regimens used to address tear insufficiency and inflammation, and—consistent with the nasal route—reported adverse events are chiefly non-ocular^3,6-7.

This rationale for “tear film restoration” aligns well with the staged, evidence-based framework proposed by TFOS DEWS for dry eye management. In this model, treatment is introduced progressively and adapted to the specific dry eye subtype as well as to the mechanisms driving the disease. Early management focuses primarily on measures that restore, preserve, and enhance the tear film, while also addressing the eyelids when meibomian gland dysfunction is part of the clinical picture. Anti-inflammatory therapy, by contrast, is introduced when inflammation or other defined etiological factors play a relevant role^6,32. Within this framework, nasal neurostimulation should be viewed as an emerging adjunctive strategy rather than a broad replacement for established anti-inflammatory treatments or lid-directed therapies³². Its rationale is biologically plausible, given that lacrimal secretion is tightly regulated by neurosensory pathways: sensory stimulation from the ocular surface can trigger reflex parasympathetic activation of the main lacrimal gland³. TFOS DEWS III also places particular emphasis on patient education and long-term adherence, both of which are essential when treatment requires a stepwise and sustained therapeutic approach³².

A related practical issue is endpoint selection and interpretation. Epidemiological evidence highlights that dry eye signs are often more prevalent and more variable than symptoms, and that patient-reported questionnaires differ in their utility, together implying that objective findings and symptom burden may not align in a uniform way across populations⁴. Accordingly, when an intervention is intended to “stimulate” the tear film³² through reflex pathways³, any observed physiological change in tear dynamics should be considered one dimension of therapeutic effect and interpreted alongside patient-reported outcomes and other clinical signs, rather than assumed to translate consistently into symptom improvement for all individuals ^4,32.

4.2. Pharmacological intranasal neuroactivation: strengths and limits of the OC-01 evidence base

Across the randomized, double-masked, vehicle-controlled ONSET program, varenicline solution nasal spray (OC-01) produced statistically significant gains in tear production vs. vehicle as assessed by anesthetized Schirmer testing. In ONSET-1 (Phase 2b), the 0.03 mg and 0.06 mg twice-daily doses showed larger day-28 improvements than vehicle (least-squares mean differences of 7.7 mm and 7.5 mm, respectively; both p < 0.001), while the vehicle arm also demonstrated a measurable increase in Schirmer score over the same interval⁸. In ONSET-2 (Phase 3), a significantly higher proportion of participants achieved a ≥10 mm Schirmer improvement at week 4 with OC-01 (47.3% for 0.03 mg; 49.2% for 0.06 mg) than with vehicle (27.8%; p < 0.0001 for both), and mean Schirmer change from baseline was also greater with OC-01 than with vehicle⁹.

Symptom outcomes were supportive but not uniformly significant across doses and testing contexts. In ONSET-1, the eye dryness score improved vs. vehicle at day 28 for the 0.03 mg dose (p = 0.021), whereas the 0.06 mg dose showed a non-significant difference on Day 28; both doses showed improvements vs. vehicle for eye dryness score measured in a controlled adverse environment at Day 21⁸. In ONSET-2, eye dryness score improved with OC-01 compared with vehicle, with nominal significance reported for clinic-based measurements, whereas differences for controlled adverse environment measurements at Week 4 were not significant⁹. Corneal fluorescein staining effects were exploratory and not powered for formal comparisons in ONSET-1 and were not statistically significant vs. vehicle in ONSET-2 (despite directional improvements described for some analyses)^8-9.

Mechanistically, the intranasal approach is framed around trigeminally mediated reflex pathways that can activate lacrimal secretion via parasympathetic efferent—consistent with TFOS DEWS II descriptions of neural regulation of lacrimation^3,8-9. Practical constraints of the current evidence include the short treatment window (4 weeks in both ONSET-1 and ONSET-2), incomplete characterization in ONSET-1 of how long tear production remains elevated after dosing, and a high frequency of predominantly mild, non-ocular treatment-emergent adverse events (notably sneezing and cough) compared with vehicle^8-9. Additionally, ONSET-2 did not use a placebo run-in period and allowed as-needed artificial tear use, while still showing a substantial vehicle response on the categorical Schirmer endpoint⁹.

Post hoc analyses and evidence syntheses have expanded the view beyond the pivotal RCT readouts. In a PRISMA-guided systematic review that included full-length randomized controlled studies and post hoc analyses published between December 2021 and September 2023, OC-01 varenicline nasal spray showed outcomes consistently favoring active treatment over vehicle for anesthetized Schirmer testing and for symptom scoring on an eye-dryness visual analog scale; total corneal fluorescein staining also favored OC-01 in the studies that reported it. At the same time, the authors emphasized that the incremental benefit over vehicle for symptom scores can warrant cautious interpretation when considering thresholds for clinical meaningfulness²¹. In parallel, the FDA’s cross-discipline review of NDA 213978 concluded that efficacy evidence was consistent for Schirmer-based endpoints across the development program, whereas symptom reduction reached statistical significance in ONSET-1 but was not confirmed in ONSET-2. From a regulatory perspective, in October 2021 the FDA granted approval for TYRVAYA (varenicline solution) nasal spray with the indication of treating the signs and symptoms of dry eye disease¹¹.

Tolerability has largely been shaped by adverse events linked to the intranasal route rather than ocular events. In ONSET-1, OC-01 was associated mainly with sneezing and cough, described as transient and predominantly mild⁸. In ONSET-2, most treatment-emergent adverse events were likewise characterized as mild and non-ocular—particularly sneezing, cough, throat irritation, and instillation-site irritation—and these were reported by fewer patients in the vehicle group than in the OC-01 groups⁹. Consistently, a systematic review and meta-analysis of three randomized trials found no significant differences vs. placebo in serious adverse events or ocular adverse events, while nasal cavity–related adverse events—most notably cough and throat irritation—were increased with varenicline nasal spray¹¹. In an integrated analysis focused on safety, adherence, and discontinuation across three trials (1061 randomized), 93.5% of participants receiving varenicline nasal spray completed the treatment period despite treatment-emergent adverse events, indicating high trial completion¹².

Real-world pharmacovigilance can add complementary context, but interpretation must remain cautious. In a population-based FAERS disproportionality analysis (inception to April 2024) using reporting-odds ratios with nasal saline and Systane as controls, no disproportionate reporting of specific ocular adverse events was observed vs. nasal saline; compared with Systane, higher odds were reported for lacrimation, visual impairment, and photophobia. The authors explicitly note that a direct causal relationship cannot be established and discuss structural limits of FAERS (including voluntary reporting, potential reporting biases, and the absence of exposure denominators for incidence estimation)²².

Two interpretive caveats help keep the Discussion balanced. First, neuromodulation via nasal neurostimulation is presented as an emerging approach designed to stimulate the tear film, but dry eye disease is multifactorial and management frameworks also emphasize targeted treatment of meibomian gland dysfunction (a major contributor), lid abnormalities/hygiene measures, and—when relevant etiological drivers are present—anti-inflammatory therapies; therefore, tear stimulation alone may not address all components of disease^2,6,32.

Second, the safety and performance of repeated, long-term intranasal administration still warrant careful evaluation, and response in routine use may vary because delivery efficiency is highly sensitive to nasal physiology (the mucus/mucin barrier and rapid mucociliary clearance, including in conditions such as rhinitis), inter-individual differences in nasal geometry, and user/device-dependent deposition in the upper nasal/olfactory region^16-17,25.

4.3. Device-based intranasal tear neurostimulation: supportive signal with heterogeneity

Evidence from early single-arm work and subsequent controlled/pivotal studies supports the physiological rationale that intranasal microcurrent stimulation of the nasal mucosa can activate the nasolacrimal pathway and acutely increase tear production as measured by Schirmer testing^13-14. In a prospective open-label pilot study in dry eye disease, stimulated Schirmer scores exceeded unstimulated values at all visits, accompanied by reductions in staining and symptom scores over follow-up, with no serious device-related adverse events reported¹³. In the pivotal program, a randomized double-masked crossover study showed substantially higher Schirmer scores during active intranasal stimulation than during extra nasal active control or sham intranasal applications, and in the 180-day open-label study stimulated Schirmer values remained higher than pre-stimulation (unstimulated) values at multiple time points; symptom measures improved at selected visits and most participants reported symptoms as better or somewhat better at day 180, while changes in corneal staining were not consistently observed across regions/time points¹⁴. At the evidence-synthesis level, a meta-analysis pooling randomized, and non-randomized trials found significantly higher Schirmer II scores after intranasal tear neurostimulation but also reported very high between-study heterogeneity for this endpoint, reflecting variation across included trials¹⁵. A broader systematic review/meta-analysis that combined electrical and chemical approaches to trigeminal–parasympathetic pathway stimulation likewise found improvements in Schirmer testing and symptom scores on average but emphasized substantial heterogeneity and a low overall certainty of evidence; adverse events were more frequent than in inactive/low-activity controls yet generally described as mild and tolerable³³.

Clinically, neuromodulation devices introduce real-world considerations that are familiar from other DED interventions, including tolerability, sustained adherence with repeated use, and the continuing difficulty—given the current evidence base—of predicting which patients or DED subtypes will reap the greatest benefit^6,34. The TFOS DEWS II pain and sensation report highlights that neurosensory abnormalities are relevant to DED pathophysiology and that reflex regulation of lacrimation depends on sensory input to the lacrimal functional unit, providing a biological rationale for approaches that engage neural pathways in selected patients³. In line with this framework, reviews of ocular neurostimulation describe neuromodulation as an emerging strategy that can leverage the nasolacrimal reflex as an alternative pathway to increase lacrimation and potentially influence additional tear-film components, while acknowledging that key aspects of innervation and stimulation as a therapeutic target remain incompletely understood and warrant further study²³. Expert consensus work using a modified Delphi process has likewise converged on restoring natural tear production as a primary treatment goal and views neuromodulation—by rapidly stimulating natural tears—as a promising option to help address unmet needs, while also emphasizing the importance of additional evidence on longer-term effectiveness, patient-reported outcomes, adherence, and safety³⁴.

4.4. Extending the concept: intranasal delivery as a platform for optic nerve/retinal neuroprotection

An important extension of intranasal approaches is their use as a non-invasive route to deliver protein-based biologics to ocular neural tissues. In preclinical studies, intranasal administration of ST266—an amnion-derived cell secretome containing multiple growth factors and anti-inflammatory cytokines—was reported to accumulate in the eye and optic nerve and to preserve visual function and retinal ganglion cells in experimental optic neuritis, alongside reductions in optic nerve inflammation and demyelination^18-19. Similar neuroprotective signals were also described after traumatic optic nerve injury, where daily intranasal ST266 attenuated optokinetic response decline and reduced optic nerve axon/myelin damage while limiting retinal ganglion cell loss²⁰. Fractionation experiments further suggest that these effects are not fully reproduced by lower molecular weight components alone: removing proteins >50 kDa preserved some myelin-protective activity but diminished retinal ganglion cell protection and in vitro proliferative effects compared with unfractionated ST266, indicating that the complete secretome composition contributes to optimal neuroprotection²⁹.

Additional preclinical studies also illustrate the feasibility of intranasal delivery to the posterior segment. In an MNU-induced murine model of retinal degeneration, intranasal erythropoietin (EPO) produced significantly higher retinal EPO concentrations than intravenous administration and was associated with stronger functional and structural rescue, including better preservation of ERG responses and retinal architecture, reduced photoreceptor apoptosis, and rescue of cone populations³⁰. In a separate EAE optic neuritis model, daily intranasal nanoparticles significantly increased retinal ganglion cell survival compared with intranasal vehicle, whereas unconjugated intranasal resveratrol showed only a non-significant trend; notably, the RGC-sparing effect occurred without significant reductions in optic nerve or spinal cord inflammation/demyelination³¹.

More broadly, nose-to-brain delivery via olfactory and trigeminal pathways is viewed as feasible but constrained by nasal physiology (mucus interactions, mucociliary clearance and enzymatic degradation) and by human anatomical limitations (restricted dosing volumes and limited olfactory surface), so these reviews emphasize the need for optimized formulations and delivery approaches (e.g., nanoparticles, gels and permeation enhancers), alongside rigorous long-term safety assessment and clearer regulatory frameworks for chronic/repeated use^35-38.

However, the translation gap is substantial and should be stated plainly. As Chiang and Hsu emphasize, achieving therapeutic concentrations at the optic nerve head is inherently difficult because this tissue is extremely small and anatomically protected by the blood–retina and blood–brain barriers; accordingly, commonly used routes (topical drops, intravitreal, retrobulbar, and systemic delivery) are often not expected to dose the optic nerve head/optic nerve adequately while keeping exposure elsewhere low, and systemic dosing may require higher doses that increase the risk of whole-body side effects. Even when optic nerve head exposure is reported after intravitreal or systemic administration, they note that, without understanding distribution across other ocular tissues, it can remain unclear whether true targeting of the optic nerve head has been accomplished. Finally, they caution that preclinical testing—especially in rodents—may be useful for identifying targets but is unlikely, by itself, to yield a route of administration that is practical and safe for humans, reinforcing the broader need for delivery technologies and drug designs that can provide localized, targeted, and clinically feasible optic nerve dosing³⁹.

4.5. Why delivery efficiency is not guaranteed: anatomy, clearance, and deposition variability

Even if direct nose-to-brain transport is mechanistically plausible via olfactory and trigeminal pathways, practical determinants make delivery efficiency difficult to reproduce. In humans, the olfactory epithelium accounts for <10% of total nasal surface area (vs. ~40–50% in rats/mice), and conventional nasal spray pumps deposit only a small fraction of the dose in the upper nasal space/olfactory region (reported at ~5% in one review and <3% in another), limiting consistent targeting and complicating translation from animal studies. Drug residence is further constrained by mucociliary clearance: the nasal mucosa’s ciliary transport (reported around 6 mm/min) and overall clearance on the order of ~10–20 min shorten contact time and can reduce retention of intranasally administered formulations, particularly liquids. Formulation strategies that increase viscosity (e.g., gels or in situ gelling systems) are discussed as ways to extend intranasal retention relative to simple solutions, though clearance remains a relevant loss mechanism^16-17.

Finally, where formulation deposits are sensitive to individual nasal geometry, administration technique, and formulation properties (including viscosity and particle-related factors), introducing additional variability in exposure at target regions. Keller et al. note that formulation viscosity can influence nasal spray droplet size and, consequently, the intranasal deposition site, adding another source of inter- and intra-subject variability²⁵. Because intranasal products directly contact the nasal mucosa, reviews emphasize that safety assessment should consider not only the active drug but also excipients and other formulation components, with attention paid to effects on ciliary function, local irritation, and potential CNS-related toxicity endpoints^16-17,25.

More recent delivery-system reviews described formulation and device approaches—such as mucoadhesive polymers, stimulus-responsive/in situ gelling systems, and nano-/lipid carriers, alongside delivery devices designed to increase deposition in upper nasal regions—intended to prolong nasal residence and improve brain exposure after intranasal dosing; they also emphasize that these strategies add formulation-dependent variables and that translation depends on rigorous safety evaluation (including long-term nasal/neuronal endpoints), as well as addressing stability/scale-up challenges and navigating gaps in regulatory guidance specific to CNS-targeted nasal products^35-38. CFD evidence syntheses indicate that olfactory deposition outcomes vary widely across simulations and are not driven uniformly by a single “device setting”: in meta-analytic pooling, smaller particle size and lower particle inertia (captured by the impaction parameter) show consistent associations with higher olfactory deposition, whereas breathing flow rate exhibits no consistent relationship; the review also reports substantial between-study heterogeneity and differences in model definitions/assumptions, supporting the interpretation that nominally similar administrations can attain different effective delivery to the olfactory region across scenarios²⁷.

Consistent with this focus on local safety, meta-analyses of inhaled and/or intranasal corticosteroid exposure have not demonstrated a significant increase in glaucoma or ocular hypertension incidence vs. controls; however, some pooled analyses report slightly higher mean intraocular pressure in users compared with untreated patients (without a significant rise from pretreatment baseline), and randomized trials of intranasal corticosteroids reported zero glaucoma cases at 12 months with only a small absolute increase in elevated intraocular pressure compared with placebo^40-42.

Liposome-focused intranasal work illustrates the same design trade space: while nose-to-brain delivery is actively pursued as a non-invasive alternative to invasive CNS routes, and nanocarriers such as liposomes are investigated as a way to enhance intranasal delivery, brain distribution is not necessarily improved; in the liposome study by Tsuji et al., the surface properties of intranasally administered liposomes measurably influenced tissue distribution and, when surface-modified liposomes were used, the model cargo showed elevated concentrations at the ocular limbus, supporting the feasibility of targeting drug delivery to posterior ocular regions—particularly the optic nerve—via intranasal administration⁴³.

4.6. Safety and monitoring: beyond short-term tolerability

Short-term safety data for intranasal varenicline (OC-01) in dry eye disease are broadly reassuring in controlled trials, with tolerability largely shaped by non-ocular, route-related events such as sneezing and cough; in ONSET-1, sneezing was common (62%–84%) and cough occurred in 9%–25%, and these events were described as transient and predominantly mild. (8,9) In consistency with this, a systematic review/meta-analysis of randomized trials found no significant difference vs. placebo in serious adverse events or ocular adverse events, while nasal cavity-related adverse events (notably cough and throat irritation) were increased; trial-level safety analyses also reported high treatment completion (>93%) despite treatment-emergent adverse events^11,12. Because intranasal therapies for DED may be used over longer periods, continued longer-term monitoring remains relevant. As a broader reference point for chronic intranasal exposure, adult intranasal corticosteroid safety meta-analyses report an overall favorable safety profile with no persistent abnormalities in cortisol levels or intraocular pressure, but a significantly increased risk of epistaxis vs. control—underscoring that local mucosal effects warrant attention even when systemic/ocular signals are limited⁴¹. From an ophthalmic standpoint, a systematic review/meta-analysis of randomized controlled trials in patients with rhinitis found that intranasal corticosteroid use was not associated with a statistically significant increase in elevated intraocular pressure (IOP) and reported zero glaucoma cases at 12 months in both intranasal corticosteroid and placebo groups; the absolute increased incidence of posterior subcapsular cataract was also very low. The authors further note that IOP is an imperfect surrogate for glaucomatous optic nerve damage and recommend that future studies formally evaluate glaucoma, highlighting limited generalizability because patients at highest risk for glaucoma progression were excluded from the included trials⁴². In parallel, a systematic review/meta-analysis of inhaled and intranasal corticosteroids reported no significant difference in glaucoma incidence or ocular hypertension incidence vs. controls, but did observe a small, significantly higher IOP in corticosteroid users in comparison with untreated controls; no significant IOP increase was observed within users vs. pretreatment baseline. The authors emphasize that awareness of these findings is important in the care of patients with additional glaucoma risk factors and suggest that patients should be advised to seek regular examinations with an eye care professional when these medications are prescribed⁴⁰.

For intranasal DED therapies, these corticosteroid datasets do not establish long-term ocular safety, but they provide context on outcomes reported with intranasal exposure in adults: a safety meta-analysis of intranasal corticosteroids found no persistent abnormalities in cortisol levels or intraocular pressure, while identifying a significantly increased risk of epistaxis vs. control⁴¹. More broadly, an intranasal drug-delivery review highlights that, alongside formulation limitations, toxicological considerations of intranasally applied compounds and formulation development issues require attention during drug development²⁵. Taken together, the evidence supports a risk-informed approach that keeps local nasal adverse events (including epistaxis) in view and maintains ophthalmic awareness—particularly for patients with additional risk factors for glaucoma—when chronic intranasal therapies are contemplated^25,40-42.

4.7. Research priorities to strengthen the field

Several priorities emerge from integrating the DED and delivery/neuroprotection literatures:

• Standardized pharmacokinetic (PK) and safety evaluation after intranasal administration, supported by harmonized, validated, and reproducibly reported methods (including stronger standardization/validation in deposition modeling studies), and—when feasible—imaging- or tracer/marker-based approaches to track distribution from the nasal cavity toward intended CNS targets and to refine translation^{16-17,25–28,35,38}.
• Rigorous comparative evaluation vs. established DED care—e., studies designed with appropriate masking, randomization, and controls to benchmark emerging interventions against the current staged, etiology-informed management framework (with ocular supplements as a cornerstone and escalation to lid, anti-inflammatory, biological tear substitutes, and advanced options as indicated), while also capturing patient-facing factors such as education and adherence that influence sustained symptom relief^6,32.
• Phenotype-informed DED trials that (i) differentiate aqueous-deficient from evaporative disease when selecting and testing therapies, (ii) capture neurosensory involvement (dryness-related pain/dysesthesias and, where relevant, corneal nerve assessment tools such as questionnaires, esthesiometry, and in vivo confocal microscopy), and (iii) evaluate neuromodulation/intranasal stimulation approaches using consistent, prespecified efficacy and safety outcomes (g., symptom scores, corneal staining, tear production measures such as Schirmer testing, tear film break-up time, and reported glandular/cellular metrics used in existing syntheses), given the high heterogeneity and limitations of current evidence highlighted in meta-analyses and evidence-based management reports^3,6,15,33-34.
• Long-term, post-marketing safety registries for chronic intranasal therapies, with standardized collection of nasal safety signals (including local irritation symptoms and epistaxis) and structured ocular surveillance (spontaneously reported ocular events such as lacrimation/photophobia/visual impairment where applicable, plus monitoring of intraocular pressure–related outcomes and formal evaluation for clinically meaningful glaucoma/cataract when relevant), particularly in patients with comorbid conditions or concomitant inhaled/intranasal corticosteroid exposure^22,25,40-41.
• Formulation and device optimization should be grounded in deposition science, including CFD evidence that particle characteristics (notably size) and inertia-related metrics (impaction parameter) are key determinants of olfactory-region depositions supporting iterative device/design optimization and the need for standardized reporting/validation across studies. In parallel, optimization should address practical nasal constraints that can undermine reliable dosing (g., limited instillation volume and rapid clearance) by leveraging delivery strategies such as permeability enhancers, gelling approaches, and nano/lipid carriers, with size and surface attributes tuned for mucus and cellular permeability; designs should also reflect ease of use and patient compliance considerations associated with intranasal administration^{27,35–38,43}.

Taken together, the clinical evidence supports intranasal neuroactivation as a meaningful, non-ocular-surface route to improve tear production in DED, while translational neuroprotection remains an exciting but still preclinical frontier that will require rigorous PK/PD validation and careful trial design to avoid overinterpretation of early signals.

4.8. Limitations

The findings of this review should be interpreted within the limits inherent to a narrative approach. Although the search strategy and the rationale for study selection were defined in advance, this work was not conducted as a systematic review, did not include a formal risk-of-bias assessment, and was not designed to generate a new meta-analysis. As a result, study selection and interpretation inevitably remained influenced, at least to some extent, by author judgment. This also means that a degree of selection bias cannot be fully excluded, particularly in the prominence given to selected preclinical models and to specific proof-of-concept intranasal candidates.

Another important limitation lies in the marked heterogeneity of the available evidence. The studies included in this review differed substantially in design, patient or experimental populations, interventions, outcome measures, and duration of follow-up. This variability makes direct comparisons difficult and prevents any robust quantitative comparison across treatment modalities. In particular, while both pharmacological intranasal neuroactivation and device-based intranasal neurostimulation yielded encouraging results in terms of tear production, the current evidence does not support firm conclusions about their relative efficacy or comparative clinical value.

It should also be emphasized that the preclinical section was intended as a translational proof-of-concept overview focused on studies reporting ocular or optic nerve relevance after intranasal administration, rather than as an exhaustive systematic appraisal of all intranasal neuroprotective strategies. Collectively, these limitations call for caution when interpreting the apparent consistency, strength, and broader translational implications of the evidence, especially with respect to ocular neuroprotection.

5. Conclusions

Dry eye disease (DED) is a common, multifactorial condition in which loss of tear-film homeostasis is the central pathophysiological concept, with tear-film instability/hyperosmolarity, ocular-surface inflammation and damage, and—based on newer evidence—neurosensory abnormalities all recognized as key contributors. Epidemiological syntheses report a wide prevalence range (about 5%–50%) and note that signs are often more prevalent and more variable than symptoms, aligning with the recognized clinical spectrum in which signs and symptoms may not match (including presentations with signs but minimal symptoms, or symptoms without demonstrable ocular-surface signs)^1–6. Intranasal pharmacologic stimulation of endogenous tear production via neuroactivation of the nasolacrimal reflex (also described as the trigeminal parasympathetic pathway) represents a newer therapeutic approach for DED that avoids direct topical instillation on the ocular surface. In randomized, double-masked, vehicle-controlled studies, varenicline solution nasal spray produced statistically significant improvements in tear production measured by anesthetized Schirmer testing over 4 weeks, with both ONSET-1 and ONSET-2 meeting tear-production efficacy outcomes vs. vehicle. Across these clinical programs and post hoc syntheses, tolerability has been largely shaped by non-ocular, nasal-route events—most commonly transient, predominantly mild sneezing and cough—while pooled analyses did not detect a significant increase in serious adverse events or ocular adverse events vs. placebo^7–12. Device-based intranasal tear neurostimulation has likewise been shown to elicit a consistent increase in stimulated tear output. In a prospective, open-label pilot study, stimulated Schirmer scores were significantly higher than unstimulated values at each assessment time point, and no serious device-related adverse events were reported¹³. In two pivotal clinical trials—including a randomized, double-masked crossover study and a 180-day open-label cohort—active intranasal stimulation produced markedly higher Schirmer scores than sham or active-control applications, and the stimulated-minus-unstimulated Schirmer difference remained significant at Day 180; the investigators noted that staining and symptom measures improved at selected time points but were not uniformly consistent across outcomes and follow-up¹⁴. Complementing these trial data, a meta-analysis pooling 17 clinical trials found significantly higher Schirmer II scores after intranasal tear neurostimulation, with reported adverse events described as mild-to-moderate and no serious adverse events observed¹⁵.

Beyond tear stimulation, intranasal administration is increasingly being explored as a non-invasive “nose-to-brain” delivery approach that can bypass the blood–brain barrier by exploiting transport along the olfactory and trigeminal nerve pathways. Preclinical pharmacokinetic studies summarized in recent reviews also indicate that, after intranasal dosing, drug exposure can be detected not only across multiple brain regions but also in cranial-nerve–associated structures such as the trigeminal nerve and the optic nerve^16-17. Preclinical studies with the amnion-derived secretome ST266 support the feasibility of functional and structural neuroprotection in rodent models of optic nerve/retinal injury (experimental optic neuritis and optic nerve crush), including preservation of optokinetic visual responses and reduced retinal ganglion cell loss with accompanying reductions in optic nerve inflammation and demyelination. However, these findings remain preclinical, and their translational weight is limited because ocular exposure after intranasal dosing has been demonstrated in rodents, while comparable human ocular distribution/pharmacokinetics and confirmation of relevant pathway/target engagement in humans have not yet been established^18–20.

Importantly, intranasal efficacy depends on reliable deposition onto the nasal mucosa to activate trigeminal sensory pathways that drive the nasolacrimal reflex and lacrimal functional unit, yet the clinical literature to date has not routinely incorporated nasal endoscopic screening to exclude nasal conditions that might alter spray administration or absorption, and key outcomes have largely been assessed around the time of dosing—so delivered exposure and the durability of response may vary meaningfully across individuals^21–24. These limitations—especially the difficulty of reliably targeting the olfactory region, the safety liabilities that can arise from formulation components (including excipients and absorption enhancers) and from nanocarriers, and the still-debated strength of human nose-to-brain evidence—argue for standardized, quantitative deposition/targeting studies, rigorous toxicological evaluation of all formulation constituents, and robust biodistribution plus PK/PD characterization before intranasal platforms are advanced as credible CNS-directed therapeutic strategies^25–28. Additional intranasal proof-of-concept studies—including the amnion-derived secretome ST266, intranasal erythropoietin delivery in a retinal degeneration model, and intranasal resveratrol nanoparticles in EAE—support the feasibility of intranasal delivery to the retinal/optic nerve and demonstrate neuroprotective effects in these settings. Across these models, responses appear sensitive to formulation and dose (e.g., diminished neuroprotection after removing >50 kDa ST266 components; higher retinal EPO levels with comparatively lower systemic exposure than intravenous dosing; significant RGC preservation with intranasal resveratrol nanoparticles), underscoring the value of quantifying local exposure and using objective functional/structural endpoints to link delivery to effect^29–31.

Within stepwise DED management algorithms, intranasal neuromodulation (e.g., nasal neurostimulation or varenicline nasal spray) is described as an emerging approach aimed at stimulating patients’ natural tear production and can be considered as part of etiologically-guided care. Evidence synthesized from randomized trials shows improvements in tear secretion outcomes, and the frequent requirement for demonstrable secretory responsiveness in study populations suggests greater suitability for tear-deficient patients with preserved lacrimal secretory potential. In parallel, expert consensus supports integrating neuromodulation into DED treatment algorithms as an additional mechanism addressing tear deficiency, alongside established lid- and anti-inflammatory strategies when indicated by the underlying drivers of disease^32–34. Recent reviews described rapid progress in intranasal nose-to-brain delivery, moving beyond simple solutions toward optimized platforms (e.g., permeability enhancers, gelling/in-situ gel systems, and nano-carrier formulations) and improved intranasal devices intended to enhance deposition, retention, and targeting. In parallel, emerging work on optic nerve/optic nerve head delivery is outlining potential targeted routes and technical approaches, while also emphasizing remaining translational uncertainties. Across both areas, clinical translation will likely depend on more standardized, clinically meaningful measures of target-tissue exposure and biodistribution (not relying mainly on surrogate endpoints such as CSF levels), alongside rigorous long-term safety evaluation and well-controlled studies that can clarify comparative performance and risk profiles^35–39.

Given the expectation of chronic administration in DED, long-term follow-up should include surveillance for nasal adverse events (e.g., epistaxis) and regular ophthalmic monitoring; although systematic reviews/meta-analyses do not show a significant increase in glaucoma or ocular hypertension incidence with inhaled or intranasal corticosteroids, small differences in IOP vs. non-users have been reported, so IOP assessment—and, when clinically indicated, formal evaluation for glaucoma rather than relying on IOP alone—may be prudent, especially in patients with additional glaucoma risk factors^40–42. Recent formulation work on intranasal liposomes indicates that delivery can be influenced by design choices—such as producing ~100-nm carriers to better traverse the nasal mucosal mesh and using surface modifications aimed at improving mucus permeation (PEG) or cellular interaction (R8)—with detectable differences in distribution to brain and ocular tissues, including signals consistent with posterior ocular/optic nerve reach; overall, it emphasizes that further refinement of intranasal delivery techniques is pivotal for future clinical application⁴³. Recent reviews and scoping syntheses map the key nose-to-brain pathways (including olfactory and trigeminal routes), summarize advanced formulation and platform options (e.g., nanocarriers, microemulsions, in-situ gels, powders, and nano emulsions), and integrate device/deposition evidence (including bi-directional systems that can increase deposition in superior/posterior nasal regions such as the olfactory cleft). Collectively, they converge on practical development priorities for clinically translatable intranasal products: improving targeting efficiency and bioavailability while addressing mucociliary clearance, mucosal permeability and enzymatic degradation, and strengthening translation through attention to delivered dose at the target, biodistribution, long-term safety/toxicity, manufacturability/stability, and regulatory hurdles^44–52.