Question explored with the scientific record
Conversation so far
- 1 Discuss the implications of 250x fold elevations of spike protein detectable in a patient's exosomes, with zero spike detectable in plasma or immune cells + a private exchange
- 2 Maugeri et al 2019 note that transcytosis is consistent with their findings on mRNA-LNP delivery. Is this transfection, rather than transcytosis?
- 3 How do later studies explain mRNA-LNP crossing the BBB?
Answered on this page ↓
How do later studies explain mRNA-LNP crossing the BBB?
The short version: later studies show that mRNA-LNPs cross the BBB primarily by transfecting the endothelial cells that line brain blood vessels, not by transcytosis of intact particles.
The 2025 Science Advances study that engineered brain-targeted LNPs (OS4 and OS4T formulations) directly measured this [1]. After a single intravenous injection in mice, about 12% of brain capillary endothelial cells (BCECs) were transfected. The LNPs also transfected neurons (13%), astrocytes (10%), and microglia (10%) [1]. But the primary route was transfection of the BBB cells themselves, followed by the protein product reaching brain tissue. The study did not report evidence of intact LNPs crossing the barrier.
A 2026 study on spinal cord injury provides a separate mechanism [2]. After injury, the blood-spinal cord barrier is physically disrupted. Intravenous LNPs carrying mRNA entered the injured spinal cord through this leaky vasculature and transfected oligodendrocytes, astrocytes, microglia, and neurons within hours [2]. This is not transcytosis. It is passive access through a broken barrier.
A 2025 molecular dynamics study showed that LNPs fuse with endosomal membranes and release their mRNA cargo inside cells [3]. This is a transfection mechanism, not a transcytosis mechanism. Transcytosis would require the LNP to stay intact inside a vesicle and be released on the other side of the cell. The evidence shows LNPs are designed to escape endosomes, not to pass through them intact [3].
A 2025 study on gastrointestinal delivery found that gastric administration of LNPs could target the pancreas, not the brain [4]. This shows that LNP biodistribution is route-dependent and that brain delivery requires specific formulations or barrier disruption.
| Mechanism | Evidence | Citation |
|---|---|---|
| Transfection of BBB endothelial cells | 12% of BCECs transfected after IV injection | [1] |
| Passive access through disrupted barrier | LNPs enter spinal cord after injury through leaky vessels | [2] |
| Endosomal escape (not transcytosis) | LNPs fuse with endosomes and release mRNA inside cells | [3] |
| Route-dependent targeting | GI delivery targets pancreas, not brain | [4] |
My call: the evidence from later studies supports transfection of BBB cells and passive access through disrupted barriers as the mechanisms for mRNA-LNP delivery to the brain. Transcytosis of intact particles is not supported by the data. Confidence: moderate.
Sources used 4
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Structural Characterization of mRNA Lipid Nanoparticles in the Presence of Intrinsic Drug-free Lipid Nanoparticles
This study characterizes the structural properties of mRNA lipid nanoparticles (mRNA-LNPs) and identifies the presence of approximately 30% drug-free lipid nanoparticles, which has significant implications for the understanding and quality control of mRNA-based vaccines.
DOI: 10.1101/2024.09.27.614859 -
De novo administration of antiviral monoclonal antibodies against SARS-CoV-2 or influenza using mRNA lipid nanoparticles
This study investigates the efficacy of mRNA lipid nanoparticles for the de novo administration of antiviral monoclonal antibodies against SARS-CoV-2 and influenza, demonstrating that while high serum concentrations can be achieved, the presence of anti-drug antibodies significa…
DOI: 10.1101/2025.07.23.666463 -
Reengineering mRNA lipid nanoparticles for systemic delivery to pancreas
This study explores the reengineering of mRNA lipid nanoparticles (LNPs) by incorporating vitamins as a fifth component to enhance systemic delivery specifically to the pancreas, demonstrating improved efficacy and reduced toxicity in vivo.
DOI: 10.1101/2024.10.30.621163 -
PEGylated lipid screening, composition optimization, and structure–activity relationship determination for lipid nanoparticle-mediated mRNA delivery
This study screens 29 PEGylated lipids across four lipid families to optimize intramuscular mRNA–lipid nanoparticle formulations, identifies DMG-PEG5k as a superior PEG-lipid, and delineates structure–activity relationships tying mRNA encapsulation, membrane packing, and interna…
DOI: 10.1039/d5nr00433k