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?
- 4 You stated earlier that, "Transcytosis would mean the intact LNP crosses the BBB and then transfects brain cells (neurons, astrocytes, microglia) on the other side. Transfection of the BBB means the LNP is taken up by the endothelial cells that line the brain's blood vessels, the mRNA is translated inside those cells, and the protein product is what gets released into the brain." Following up -"what exact evidence do they use to rule out intact LNP transcytosis and why does it matter?
- 5 Either way, in this patient's case 2P S can be delivered across the BBB, by process of transcytosis at least. Explain the likely effects of such a process
Answered on this page ↓
Either way, in this patient's case 2P S can be delivered across the BBB, by process of transcytosis at least. Explain the likely effects of such a process
The short version: the 2025 brain-targeted LNP study [29] measured transfection results, not particle routes, so it cannot rule out intact transcytosis.
The 2025 Science Advances study [29] engineered LNPs that, after intravenous injection, transfected about 10–13% of neurons, astrocytes, microglia, and brain capillary endothelial cells. That is a real finding. But it measured protein expression, the output of transfection. It did not label the LNP particles themselves and track whether intact particles appeared on the brain side of the BBB. Without that tracking experiment, the study cannot distinguish between two routes: intact LNPs crossing the BBB by transcytosis and then transfecting brain cells, versus LNPs being taken up by BBB endothelial cells, the mRNA being translated inside those cells, and the protein product being released into the brain. Both routes produce the same measured result.
The key experiment that would settle this is straightforward: inject fluorescently or radioactively labeled LNPs intravenously, then look for intact particles in brain tissue or cerebrospinal fluid using electron microscopy or fractionation, while also measuring whether the signal comes from intact particles or from degraded components. That experiment is not in this retrieval set. Without it, the claim that transcytosis does not happen is an inference from the absence of evidence, not a proven finding.
The other studies in this set do not fill the gap. A 2025 study that injected LNPs directly into the striatum [28] tells you nothing about crossing the BBB from the blood. A 2026 molecular dynamics study modeled LNP movement through brain extracellular matrix [25] but assumed the LNPs were already in the brain. The rest of the retrieval is about solid lipid nanoparticles for drug delivery [12, 15, 17, 24, 26, 27, 30, 31], BBB permeability in other contexts [1–9], or LNP biodistribution to liver and spleen [10, 11, 13, 14, 16, 19–22]. None of these studies designed an experiment to detect intact LNP transcytosis across the BBB.
My call: the evidence in this retrieval set does not rule out intact LNP transcytosis across the BBB. The claim that transfection of BBB cells is the only route is based on studies that did not test for transcytosis directly. Confidence: low.
Sources used 29
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Delivering Antisense Oligonucleotides across the Blood‐Brain Barrier by Tumor Cell‐Derived Small Apoptotic Bodies
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Innate immune responses to Plasmodium falciparum disrupt the blood-brain barrier
The study demonstrates that innate immune cells activated by Plasmodium falciparum can adhere to a human 3D in vitro blood–brain barrier, triggering endothelial activation and barrier disruption via LFA-1–ICAM-1 interactions and TNF-α/IFN-γ signaling, thereby revealing an immune…
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Mesocricetus auratus (Golden Syrian Hamster) Experimental Model of SARS-CoV-2 Infection Reveals That Lung Injury Is Associated with Phenotypic Differences Between SARS-CoV-2 Variants
In golden Syrian hamsters infected with four different SARS-CoV-2 variants, the study reveals variant-specific lung injury linked to endothelial damage and innate immune responses, with Omicron causing milder pathology and A.2/Delta producing more severe injury, alongside notabl…
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Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease
Loss of mitochondrial ClpP, Lonp1, or TFAM triggers dsRNA-sensing innate immune signaling that upregulates RNF213, a Moyamoya disease susceptibility gene, across multiple cell types, suggesting a mitochondrial-nucleic acid axis linking mitochondrial stress to vascular disease ri…
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Dengue-2 Structural Proteins Associate with Human Proteins to Produce a Coagulation and Innate Immune Response Biased Interactome
This study identifies 31 human proteins that physically interact with dengue-2 structural proteins (Env, PrM, Cap) using bacterial two-hybrid screens, constructs a dengue–human interactome, and links these interactions to coagulation and innate immune pathways, suggesting dengue…
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A comprehensive review of how emerging neurotropic viruses invade the CNS, how CNS innate immunity (glia and PRRs) detects infection and how viruses counteract interferon signaling, with discussion of therapeutic targets and delivery challenges across the blood–brain barrier, in…
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Long-term Air Pollution Exposure Is Associated with Neuroinflammation, an Altered Innate Immune Response, Disruption of the Blood-Brain Barrier, Ultrafine Particulate Deposition, and Accumulation of Amyloid β-42 and α-Synuclein in Children and Young Adults
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Development of Recombinant Anti-TLR2 Antibodies and PLGA Nanoparticle-based Gene Therapy for the Treatment of Neuropathic Pain
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