After years of incremental progress, intranasal drug delivery is beginning to show the contours of a true inflection point. Once viewed primarily as a niche solution, the nasal route is now being evaluated earlier in development for systemic and central nervous system (CNS) indications—driven by recent regulatory approvals, advances in formulation and device science, and growing pressure to improve speed, usability, and real-world effectiveness of therapies.

This shift does not reflect a sudden discovery, but rather a convergence of technical readiness and strategic need. For sponsors, the question is no longer whether intranasal delivery can work, but when it makes sense—and what distinguishes viable programs from those that struggle.

Why Intranasal Delivery Matters Now

Several forces are pushing intranasal delivery from the periphery toward the center of many companies’ development strategies.

One reason for this is that traditional routes of administration present persistent limitations. Oral delivery remains subject to first-pass metabolism, GI degradation, and delayed onset, all of which can compromise effectiveness for time-sensitive indications. And injectable therapies, while often pharmacologically efficient, introduce practical barriers related to training, access, and patient acceptance and adherence. Intranasal delivery offers a non-invasive alternative capable of rapid systemic absorption, often effective at lower doses and without the need for needles or clinical infrastructure.

Regulatory momentum has further accelerated interest. A series of recent FDA approvals has demonstrated that intranasal delivery can support systemic and acute indications when appropriately designed. Needle-free epinephrine for anaphylaxis, over-the-counter naloxone for opioid overdose, intranasal migraine treatments, and most recently, self-administered nasal therapy for paroxysmal supraventricular tachycardia, all underscore the same principle: intranasal delivery is particularly well-suited to scenarios where speed, accessibility, and ease of use are as critical as pharmacology itself.

The Pharmacological Case for Intranasal Delivery

When appropriately matched to the molecule and indication, intranasal delivery offers several well-documented advantages:

• Rapid onset of action, particularly valuable for acute conditions such as migraine, cardiac arrhythmias, and emergency rescue therapies
• Bypassing first-pass metabolism, improving effective bioavailability for drugs degraded in the GI tract
• Non-invasive administration, reducing barriers associated with injections or IV access
• Flexibility in drug–device combinations, enabling lifecycle management and differentiated product profiles

These advantages are most robust for single-use or short-term dosing scenarios. Daily intranasal administration (for example, for chronic conditions) introduces additional considerations around local tolerability, device burden, and long-term adherence.

Blood–Brain Barrier: An Opportunity, not a Shortcut

Interest in intranasal delivery is closely linked to its potential relevance for CNS indications. Anatomical connections between the nasal cavity and the brain via the olfactory and trigeminal nerves create the possibility of direct nose-to-brain transport, potentially bypassing the historically difficult -to-cross blood–brain barrier. This has positioned intranasal delivery as an appealing option for developers seeking faster or more targeted CNS exposure.

Realizing this potential, however, depends on deliberate design. Only a modest fraction of an intranasally administered dose is likely to reach the brain via direct transport, even under optimized conditions. Nevertheless, small amounts can be pharmacologically meaningful, particularly for acute indications. Success requires effective deposition in the upper nasal cavity, emphasizing the importance of specialized device designs and precise plume targeting. Residence time is also critical, as rapid mucociliary clearance can limit uptake without formulation or device strategies to prolong contact.

For these reasons, nose-to-brain delivery should be viewed as a complementary mechanism rather than a replacement for systemic exposure. Its strongest rationale may lie in acute CNS conditions in which rapid, modest drug levels can translate into meaningful clinical benefit. Migraine therapies provide a practical example: intranasal delivery can accelerate CNS availability and shorten time to relief, even when systemic exposure remains an important contributor to efficacy.

Why Peptides and Biologics Are Emerging as the Next Wave

One of the most notable shifts in intranasal development is a growing interest in peptides and biologics, modalities traditionally dominated by injectable administration. Oral delivery remains poorly suited for these molecules, due to enzymatic degradation and limited permeability, making alternative non-invasive routes increasingly attractive.

Several factors are enabling this expansion. Dose efficiency is critical; biologics that achieve therapeutic effects at microgram-to-milligram levels are more compatible with nasal volume constraints. Advances in formulation science, including mucoadhesive systems, absorption enhancers, and gel-forming technologies can extend nasal residence time and improve uptake. Device innovation has also improved targeting and reduced variability, supporting more consistent exposure across patients.

Intranasal delivery is unlikely to replace injectables for most biologics. Instead, it may enable differentiated use cases – such as rapid-onset symptom relief, adjunctive dosing, or rescue therapies where injections are impractical or undesirable. Framing intranasal strategies around these roles can improve both technical feasibility and clinical relevance.

Scientific and Translational Challenges Sponsors Must Address Early

Despite its promise, intranasal delivery introduces technical challenges that can derail programs if addressed too late:

• Dose variability: Patient technique and nasal physiology can introduce greater variability than oral or IV routes.
• Volume constraints: Only limited fluid volumes can be delivered without runoff or swallowing.
• Formulation trade-offs: Enhancing absorption may come at the cost of local irritation or stability challenges.
• Species differences: Nasal anatomy varies widely across animal models in the preclinical development setting, complicating translation of deposition and PK data to humans.

Programs that succeed tend to confront these issues before IND-enabling studies, rather than attempting to retrofit solutions later.

The Role of NAMs in Modern Intranasal Development

New Approach Methodologies (NAMs) are increasingly being integrated into intranasal development—not as replacements for in vivo studies, but as decision-shaping tools.

Human nasal cast models, for example, allow sponsors to evaluate deposition patterns, device performance, and formulation behavior within anatomically realistic structures. These models can inform dose selection, compare devices, and reduce reliance on animal studies for questions that are fundamentally anatomical rather than biological.

Regulatory agencies have signaled growing openness to well-justified NAM use, particularly when employed to refine hypotheses, contextualize animal findings, or support early clinical translation. Safety assessment, however, remains firmly grounded in in vivo data.

When Is Intranasal Delivery the Right Fit?

Before committing to intranasal delivery, sponsors should be able to answer several foundational questions:

• Does the required therapeutic dose fit within realistic nasal volume limits?
• Is rapid onset or improved usability central to the product’s value proposition?
• What target site is required—systemic circulation, regional nasal tissue, or CNS exposure?
• Can formulation and device development proceed in parallel, rather than sequentially?
• How will translational risk be reduced across species and into first-in-human studies?

Defining clear answers to these questions early on can prevent costly course corrections later.

Looking Ahead: What Will Define Success Beyond 2026

As intranasal delivery expands its scope, success will be defined by execution. The programs that thrive will likely be those that select the route earlier, integrate drug and device development from the outset, move judiciously into peptides and biologics with realistic dose assumptions, and apply NAMs pragmatically to strengthen translational confidence.

Intranasal delivery is no longer an experimental detour. For the right molecules, indications, and development strategies, it represents a repeatable and regulatorily validated pathway—one that rewards sponsors who understand both its potential and its constraints.

Edward (Ted) Barrett, PhD, is Senior Director, Translational Research-Pharmacology at Lovelace Biomedical. Ted has spent most of his career investigating the effects of small molecule, biologic, nucleic acid and medical device technologies utilizing various in vitro systems and animal models of disease. His programs aim to translate nonclinical efficacy, safety, pharmacokinetic, and pharmacodynamic data obtained from species ranging from rodents to nonhuman primates to the human clinical paradigm.