Rational for IN delivery…

Reaching the brain in CNS diseases remains a major challenge in developing new therapies for neurological dysfunctions. The blood-brain barrier (BBB) blocks over 98% of potential neurotherapeutic agents, limiting the effectiveness of conventional treatments^1,2. Standard systemic administration can deliver drugs throughout the body, but this approach is invasive and often causes off-target side effects since the therapeutic also reaches non-target tissues.

Intranasal (IN) delivery provides a promising alternative: a non-invasive route that bypasses the BBB and delivers drugs directly to the CNS. The nasal cavity is highly suited for therapy delivery due to its high permeability, thin epithelial layer and large surface area. This allows absorption not only of small molecules but also of macromolecules such as proteins, peptides, nucleotides, viruses, and even stem cells².

Rethinking Brain Therapeutics: From Limitations to Solutions

Brain highways: Anatomy & pathways

This method exploits the olfactory and trigeminal nerves, which connect the nasal mucosa to the brain. Locally administered sprays can reach the CNS entry points in the cerebrum and pons, spreading through neural and extracellular routes to the target brain regions^1,3,4.

The olfactory pathway allows fast delivery, typically transporting drugs from the nasal epithelium to the olfactory bulb in under three hours. The trigeminal route reaches deeper brain regions but more slowly, reflecting the longer anatomical distance. Because intranasal administration bypasses systemic circulation, it lowers the risk of peripheral side effects while providing targeted delivery.^1,3,4.

The olfactory nerve is the most extensively studied route. Therapeutics absorbed through the olfactory epithelium are transported along olfactory nerve fibers, reaching the olfactory bulb, cerebral cortex, hippocampus and other brain regions. This pathway supports rapid absorption and high brain concentrations of drugs that would be otherwise restricted by the BBB, including macromolecules and nanoparticles^1,3,4.

Drugs follow both intracellular (endocytosis and axonal transport) and extracellular (paracellular and perineural diffusion) routes, with extracellular diffusion generally being faster. Particles sized 50–200 nm are optimal: they adhere well to nasal mucosa, cross efficiently and allow sustained release, maximizing CNS targeting while minimizing systemic exposure^1,3,4,5.

In addition to the olfactory route, the trigeminal nerve provides a complementary conduit for drug delivery. Innervating the nasal respiratory mucosa via its ophthalmic and maxillary branches, it projects to the pons and other brainstem regions. Drugs absorbed through this pathway can reach the CNS via intra-axonal transport and extracellular diffusion, independently of the olfactory route, although transport is generally slower due to the longer anatomical distance^1,3,4.

Together, these pathways form the foundation of intranasal drug delivery strategies for direct, non-invasive targeting of the CNS^1,3,4.

Why lentiviral mediated IN delivery?

Among viral systems, AAVs are the current clinical benchmark for CNS gene therapy. Unlike adenoviruses (limited by immunogenicity) or retroviruses (restricted to dividing cells), both AAVs and lentiviruses efficiently transduce non-dividing neurons, making them uniquely suited for neural delivery. Positioning our lentiviral system against AAVs allows us to highlight its advantages while engaging with the established “gold standard”. We also included nanoparticles in the comparison, as they represent the main non-viral alternative in the CNS delivery field their presence ensures that our evaluation reflects the full therapeutic landscape rather than a viral-only perspective.

Selection Logic

Lentiviral vectors stand out for CNS-targeted gene therapy because they⁶:

• Transduce non-dividingneurons effectively
• Carry large and complex transgenes (8-12kb), accommodating Morphe’s cassette
• Lack viral gene expression, reducing immunogenicity
• Fall in the 80–120 nm size range, facilitating mucosal adhesion and minimizing anterior entrapment or rapid clearance
• Allow pseudotyping , further enhancing neural tropism while enabling long-term transgene expression after a single administration⁶.

Intranasal advantage: Direct CNS access

Collectively, these anatomical features and transport mechanisms confer multiple advantages for intranasal CNS delivery^2,7:

(Hover over each card to discover more)

Today’s nasal delivery forecast

Delivering genes intranasally isn’t just about the vector, it’s about the conditions. Just as a pilot checks the weather before a flight, we check the nasal delivery weather before optimizing Morphe. Each parameter, from pH to mucociliary clearance, can create clear skies or stormy obstacles for our therapy.

The forecast dashboard

Our nasal delivery forecast shows the key factors that influence intranasal gene delivery. Some conditions are favorable, others challenging or even critical, but together, they define the landscape for success.

(Hover over each card to discover more)

Physiology – The baseline weather

These natural conditions define the starting point. We cannot control them directly, but we can design to adapt.

Formulation – Where we intervene

Formulation is where we have the most power to turn stormy skies into clear weather.

Device – Precision delivery

Even with the right formulation, delivery must hit the correct zone.

Environment – External weather

Environmental conditions are like unpredictable winds: we cannot control them, but we can prepare for them.

That being said…

By optimizing what we can (formulation and device) and adapting to what we cannot (physiology and environment), we transformed a stormy forecast into clear skies for intranasal gene therapy. This design not only bypasses the blood–brain barrier but also exploits the olfactory and trigeminal “highways” to deliver lentiviral vectors directly to the CNS. By keeping particle size in the 80–120 nm range and optimizing formulation parameters, we achieve durable expression after a single, non-invasive administration while minimizing systemic exposure.

How Morphe will address these barriers?

Intranasal delivery boosts CNS exposure while avoiding systemic toxicity, but safety concerns remain. High local viral load could provoke immune responses or neurotoxicity. While lentiviruses offer long-term gene expression after a single effective dose, comprehensive preclinical and clinical studies are still required to confirm mucosal and neuronal safety⁸.

Regulatory and translational barriers further complicate development. Neither FDA nor EMA has issued guidelines for CNS-targeted nasal delivery and current evaluations often rely on surrogate CSF measurements rather than direct brain biodistribution⁸.

Lentiviral vectors introduce additional hurdles: integration risks, immunogenicity and long-term expression concerns. Moreover, anatomical and physiological differences between animal models and humans limit predictability, as seen in intranasal insulin studies that translated poorly from rodents to Alzheimer’s patients².

Future efforts should prioritize formulation strategies that:

• stabilize lentiviral vectors in the nasal environment,
• enhance penetration across mucosal barriers and
• minimize immune activation.

Advances in computational modeling, high-resolution imaging and human-relevant in vitro models will be vital for predicting biodistribution. Scalable, cost-efficient manufacturing platforms must be developed in parallel to support clinical translation⁸.

Ultimately, precision approaches integrating systems biology and single-cell technologies could map the nasal–brain axis at unprecedented resolution, guiding the rational design of safe and effective intranasal lentiviral therapies⁸. (read more on our Future steps section)