The blood-brain barrier remains a formidable obstacle to central nervous system (CNS) drug delivery, restricting most therapeutics from entering the brain. Intranasal administration has emerged as a non-invasive alternative that bypasses this barrier via the olfactory and trigeminal nerve pathways.
However, nose-to-brain transport is severely constrained by anatomical realities. For example, the olfactory epithelium, the primary route, covers only about 3% of the nasal cavity and holds a limited volume, while the respiratory epithelium is adapted for rapid mucociliary clearance.
Consequently, most administered molecules are either systemically absorbed or eliminated. While earlier delivery systems have explored nanoparticle encapsulation to improve residence time and bioavailability, they generally offer a lower degree of delivery autonomy than the extracellular vesicle- and living therapeutic-based systems this review surveys.
This review brings together a new generation of autonomous delivery vectors that actively target the olfactory epithelium and sustain therapeutic release, organized around unified design principles of modularity, host-responsiveness, and tunability.
Synthetic Nanoparticles for Nose-to-Brain Delivery
Synthetic nanoparticles are the most extensively studied delivery systems for intranasal administration. Their modular design allows three components - the core carrier, surface modifications, and delivery module - to be independently optimized for specific payloads and targeting needs.
Polymeric nanoparticles address the challenge of mucociliary clearance, the nasal cavity's natural defense that sweeps foreign substances toward the throat. Chitosan-based nanoparticles exploit electrostatic attraction to stick to the negatively charged nasal epithelium, extending drug retention several-fold compared to non-mucoadhesive formulations.
Their synthetic counterpart, poly(lactic-co-glycolic acid) (PLGA), offers more compact and stable structures with higher drug-loading capacity, and its surface can be decorated with targeting proteins and antibodies for precise delivery.
Liposomes, with their cell-like phospholipid bilayers, excel at encapsulating diverse cargo including nucleic acids, but suffer from physical instability. Solid lipid nanoparticles provide greater structural rigidity at the cost of limited drug-loading capacity and potential drug expulsion.
Nanostructured lipid carriers address these trade-offs by blending solid and liquid lipids into an imperfect crystalline matrix, achieving higher loading, sustained release, and better long-term stability.
Preclinical studies across conditions from Alzheimer's to schizophrenia have demonstrated enhanced brain targeting and therapeutic outcomes, though surfactant-related toxicity and manufacturing consistency remain challenges for clinical translation.
Extracellular Vesicles as Autonomous Nanocarriers
Unlike synthetic nanoparticles built from scratch, extracellular vesicles are naturally secreted by all living cells and carry membrane components and bioactive cargo that mirror their parent cells. This inheritance gives them a relatively high degree of delivery autonomy, including the ability to home to specific tissues.
Direct engineering of these vesicles remains difficult, so researchers instead precondition the parent cells to enrich the cargo and surface features of the vesicles they release.
Somatic cell-derived vesicles, particularly from microglia and astrocytes, carry intrinsic neuroprotective and anti-inflammatory signals and have been used to restore microglial function in addiction models and reduce amyloid burden in Alzheimer's disease.
Macrophage-derived vesicles exploit the natural homing ability of macrophages toward inflammation and injury, showing marked improvements in motor function and neuronal survival in Parkinson's disease models.
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Mesenchymal stem cells are among the most accessible and extensively studied sources, yielding vesicles with regenerative and immunomodulatory cargo from accessible tissues like bone marrow, umbilical cord, and adipose tissue. However, donor health critically influences vesicle quality, as it was found that vesicles from obese individuals may promote neuroinflammation rather than repair.
Neural stem-cell-derived vesicles offer the greatest CNS compatibility and have demonstrated superior neuroprotection compared to mesenchymal sources in stroke models, reaching all major brain regions within 45 min of intranasal delivery. Their clinical translation, however, remains constrained by limited scalable production.
Living Therapeutics for Brain Drug Delivery
Living therapeutics are the most autonomous intranasal delivery systems, using whole organisms to navigate the nasal environment and respond to biological cues. Unlike synthetic particles or extracellular vesicles, they can be genetically programmed for sustained, localized therapeutic production.
Stem cells reach the brain through active migration along olfactory and trigeminal nerves. Mesenchymal stem cells, harvested from bone marrow, adipose tissue, and other accessible sources, have demonstrated migration to damaged brain regions within hours of intranasal administration, reducing inflammation and improving outcomes in models of Parkinson's disease, stroke, and Alzheimer's disease.
Neural stem cells offer added neurogenic potential and can be engineered to deliver anti-tumor agents selectively to glioblastoma tissue. Adeno-associated viruses provide a non-invasive gene therapy route, with different serotypes enabling region-specific brain transduction based on their capsid-receptor interactions.
Engineered commensal bacteria represent an emerging approach, with one Lactobacillus plantarum system selectively localizing to the olfactory epithelium and releasing appetite-regulating peptides that altered feeding behavior and metabolism in mice.
However, clinical translation remains challenging due to mucociliary clearance, enzymatic degradation, limited dosing volumes, and anatomical differences between rodents and humans.
Nose-to-brain entry also does not ensure delivery to the intended neural targets, highlighting the need for quantitative, region-specific assessment of therapeutic distribution and dose. Additional concerns include viral immunogenicity, stem-cell tumorigenicity, and manufacturing scalability.
Coordinated optimization of brain targeting, distribution, and long-term safety remains essential.
Advancing Intranasal Delivery Toward Clinical Translation
Intranasal delivery offers a non-invasive route to the brain that bypasses the blood-brain barrier, but its clinical potential is limited by small olfactory surface area, rapid mucociliary clearance, and inconsistent targeting.
Synthetic nanoparticles, extracellular vesicles, and living therapeutics offer increasingly active approaches to overcome these barriers. Clinical translation, however, requires reproducible dosing, precise targeting, long-term safety, and scalable manufacturing. Integrating mechanistic insights with clinically driven design will be key to making intranasal delivery a practical therapy for neurological disease.
Journal Reference
Shen, H., et al. (2026). Autonomous intranasal delivery systems for central nervous system therapeutics. Experimental & Molecular Medicine. DOI:10.1038/s12276-026-01781-5. https://www.nature.com/articles/s12276-026-01781-5.
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