In the stem cell treatment regimens for Parkinson's disease, nasal inhalation administration (such as the nasal mucosa route) is the only delivery method that does not require invasive procedures.

Nasal inhalation administration is suitable for early-stage patients (Hoehn-Yahr stage 1-2) or those who cannot tolerate surgery. It can delay the progression of the disease through multiple non-invasive treatments. Intranasal inhalation administration bypassed the blood-brain barrier through the nasal mucosa and utilized olfactory and neural pathways to deliver stem cells to the brain. It is non-invasive and easy to operate, with no surgery-related risks and extremely low operational risks.

The Phase I clinical trial of Peking Union Medical College Hospital showed that after nasal transplantation of neural stem cells, the total score of MDS-UPDRS of patients decreased by an average of 19.9 points (peak at the 6th month), and the improvement lasted until 12 months. Only minor adverse events (such as nasal mucosa irritation) were reported, and no serious complications were observed. Animal studies have shown that stem cells delivered via the nasal route can indirectly protect neurons by secreting neurotrophic factors (such as BDNF and GDNF), but the effect of directly replacing damaged dopaminergic neurons is relatively weak.

Although nasal inhalation administration is clinically effective in treating Parkinson's disease, it also has limitations. For instance, the absorption efficiency of the nasal mucosa is affected by the mucus layer and ciliary movement, and the proportion of cells actually reaching the target area is relatively low, which may require multiple repeated treatments. In animal models, only about 1% of the delivery cells were eventually distributed in the target brain regions.

The neural pathway mechanism that bypasses the blood-brain barrier

Stem cells inhaled through the nose mainly enter the central nervous system (CNS) directly through the olfactory nerve without crossing the blood-brain barrier.

The olfactory nerve originates from the olfactory epithelial cells of the olfactory mucosa in the nasal cavity. Its axons (olfactory nerve filaments) pass through the pores of the lamina cribrosa and enter the olfactory bulb, directly communicating with the cerebrospinal fluid and brain parenchyma. Stem cells or exosomes can migrate through axonal transport. After being taken up by olfactory neuroepithelial cells, they are actively transported along the axons to the olfactory bulb and then spread to more distant brain regions (such as the hippocampus and cortex). For example, mesenchymal stem cells (MSCS) can be detected in brain regions such as the olfactory bulb and hippocampus within one hour after nasal administration, indicating that the cells can rapidly migrate along neural pathways.

The indirect crossing mechanism of the blood-brain barrier

Exosomes, due to their nanoscale size (30-150 nm) and surface adhesion molecules (such as CD29 and CD63), can enter the brain parenchyma through endothelial cell transport or endocytosis of the blood-brain barrier. In brain injury or neurodegenerative diseases, the increased permeability of the blood-brain barrier may promote the entry of stem cells or the factors they secrete (such as VEGF, miRNA) into the brain.

The olfactory nerve can transfer stem cells in the nasal cavity into the brain, which is mainly related to its unique anatomical structure, physiological characteristics and the special migration mechanism of stem cells.

The fibers of the olfactory nerve (the first pair of cranial nerves) originate from the olfactory cells of the olfactory mucosa in the nasal cavity. Their axons pass through the sieve holes of the ethmoid plate and enter the anterior cranial fossa, directly connecting with the olfactory bulb of the brain. The axons of the olfactory nerve are exposed in the nasal mucosa, and the olfactory sheath cells (OECs) do not form myelin sheaths. This structural feature makes them a "natural bridge" for stem cells to enter the brain. This unique anatomical structure provides a physical channel for stem cells to migrate from the nasal cavity to the brain. Some areas of the olfactory nerve pathway (such as the lamina criposa) lack typical blood-brain barrier structures, allowing stem cells or exosomes to bypass the limitations of the blood-brain barrier and directly enter the central nervous system.

The olfactory nerve is one of the few nerves in the mammalian nervous system that have the ability to regenerate throughout life. Studies have shown that olfactory sheath cells, as supporting cells of the olfactory nerve, can encapsulate stem cells or exosomes and guide them to migrate along the axons of the olfactory nerve to the damaged areas of the brain through chemokines. Stem cells or exosomes can enter axons through endocytosis of olfactory neurons, and then be transported along the axons to the olfactory bulb, and then spread to other brain regions. Stem cells may also enter the cerebrospinal fluid (CSF) through the intercellular Spaces of the olfactory mucosa and then reach the brain through the cerebrospinal fluid circulation. Exosomes can be detected in the olfactory bulb one hour after nasal administration and distributed to the striatum and midbrain within 24 hours.

Damaged brain tissue releases chemokines (such as SDF-1), attracting olfactory nerve stem cells (ONS) or mesenchymal stem cells (MSCs) to migrate directionally to the lesion site. Stem cells can secrete enzymes such as matrix metalloproteinases (MMPs) to degrade the extracellular matrix, thereby penetrating the tissue barrier and entering nerve fibers.

Stem cells need to be located in the olfactory cleft area. After nasal administration, the patient needs to lie supine for 4 hours to promote absorption. Due to the limited distribution of stem cells in the brain after a single administration, the therapeutic effect needs to be maintained through multiple intranasal administrations (such as once a week for four consecutive weeks). Inflammation or injury can enhance the release of chemokines, which may improve the efficiency of stem cell migration. Mesenchymal stem cells (MSCs) are more likely to pass through the blood-brain barrier than neural stem cells (NSCs), but the olfactory nerve pathway may be more suitable for NSCs.

At present, the research on nasal inhalation of stem cells mainly focuses on therapeutic effects rather than transportation rates. For example, in clinical trials, the single transplantation amount of stem cells is 5×10^5/kg, and it is carried out in three sessions (with an interval of one month), but the daily transportation amount has not been clearly defined.