Pink Floyd and the Blood–Brain Barrier: Mass Spectrometry Explores How Music Modulates Protein Networks in LNP Delivery

The delivery of therapeutic agents to the brain, especially to neurons, is critical in the advancement of treatments for neurological diseases. Researchers recently introduced a non-invasive approach where music (specifically Pink Floyd’s "Another Brick in the Wall, Part 1") was used to enhance the delivery of lipid nanoparticles (LNPs) to the brain of mice, to investigate if drug uptake would improve. Mass spectrometry (MS) analysis of plasma from mice administered with messenger RNA (mRNA)-LNP intravenously and exposed to audible low-frequency sounds was performed to ascertain the level of modulation that sound stimulation provides to the proteins involved in cytoskeletal dynamics and cellular uptake. A paper based on this research was published in Journal of Controlled Release (1).

Brain diseases in general, and neurodegenerative disorders such as Alzheimer's and Parkinson's, pose a considerable obstacle in modern medicine treatments, with one of the primary obstacles being the blood-brain barrier (BBB), a highly selective barrier which restricts entry of many therapeutic agents into the brain (2,3). LNPs, emerging as a leading platform in the delivery of nucleic acids, offering protection against degradation and facilitating cellular uptake, have shown potential in systemic gene therapy, as shown by the reported success of mRNA vaccines (4-6).Their application for brain-targeted delivery, however, remains limited because of challenges relating to BBB and neuronal uptake. A variety of strategies have been tested for improving delivery of LNPs to the brain, including surface modifications with targeting ligands such as transferrin (7,8) and receptor-specific antibodies, which can guide nanoparticles to cross the BBB via receptor-mediated transcytosis (9-12). The research team, hypothesizing that the modulation of LNP cellular uptake can be achieved through low-frequency audible sound wave stimulation of neurons, proposed propose a non-invasive approach where music (audible sound, sound waves in the range of 20 Hz – 20 kHz), would be used to enhance LNP uptake (1).

In this study, different sounds were tested by the research team across frequency ranges: low (10-250 Hz), mid (160-3800 Hz), high (1250-22,000 Hz) and, as mentioned earlier, a complex 10-second soundtrack of Pink Floyd’s "Another Brick in the Wall, Part 1" (128-5600 Hz), described by the research team in their article as “atmospheric, warm, and spacious, with rich harmonics typical of the progressive rock genre. The section includes bass, ambient percussive guitar work, melodic guitar and reverb, creating a spacious, meditative atmosphere. It contrasts with the more synthesized sounds used in the experiments, offering a complex blend of live instrumentation and studio effects.” (1).

Low-frequency sound or soundtracks containing low frequencies in their spectrum achieved significantly higher nanoparticle uptake in primary cortical neurons. Specifically, exposure of primary cortical neurons to low-frequency sound (10-250 Hz) enhanced LNP uptake and transfection in neuronal cultures, resulting in a 10-fold increase in gene expression. Low frequencies are often used for mechanical cellular stimulation, which may explain the effect of specific frequency ranges to achieve higher uptake and expression. In vivo, the researchers found that mice that were administered with mRNA-LNP intravenously and exposed to audible low-frequency sounds had higher mRNA expression in the brain compared to non-exposed mice, with gene expression localized in the midbrain and thalamus, both key regions involved in sound processing and emotional regulation. MS analysis of mice plasma showed that sound stimulation modulates the abundance of proteins involved in cytoskeletal dynamics and cellular uptake. Furthermore, low-frequency sound exposure modulated the immune responses in mice, reducing neutrophil count in the blood and potentially lowering inflammation markers following intravenous LNP administration. In healthy human volunteers, functional MRI demonstrated that exposure to low-frequency audible sound elicited frontal, temporal, and occipital brain activation, in addition to the activation of classical auditory brain regions (1).

Though there is more research to be done, this preliminary proof of concept implies that music can enhance neuronal LNP uptake as well as localized brain nanoparticle distribution, which suggests that a more fundamental understanding of the role music can play in drug delivery to the brain is necessary, the scientists wrote. Additional research should further investigate the molecular mechanisms by which sound enhances cellular uptake, fine-tuning sound frequencies for different people, brain regions and cell types. They also imagine that the combination of sound with other methods (for example, BBB permeabilizers [focused ultrasound]), can possibly further improve the efficiency of delivery (1).

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References

1. Mora-Raimundo, P.; Gilon, A.; Kadosh, H. et al. Music Enhances Lipid Nanoparticle Brain Delivery and mRNA Transfection in Brain Cells. J. Control Release 2025, 388 (Pt 1), 114301. DOI: 10.1016/j.jconrel.2025.114301
2. Feigin, V. L.; Vos, T.; Nichols, E. et al. The Global Burden of Neurological Disorders: Translating Evidence into Policy. Lancet Neurol. 2020, 19 (3), 255-265. DOI: 10.1016/S1474-4422(19)30411-9
3. Wu, D.; Chen, Q.; Chen, X. et al. The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery. Signal Transduct. Target Ther. 2023,8 (1), 217. DOI: 10.1038/s41392-023-01481-w
4. Pardridge, W. M. Brain Gene Therapy with Trojan Horse Lipid Nanoparticles. Trends Mol. Med. 2023, 29 (5), 343-353. DOI: 10.1016/j.molmed.2023.02.004
5. Khare, P.; Edgecomb, S. X,; Hamadani, C. M, et al.Lipid Nanoparticle-Mediated Drug Delivery to the Brain. Adv. Drug Deliv. Rev. 2023, 197, 114861. DOI: 10.1016/j.addr.2023.114861
6. Labouta, H. I.; Langer, R.; Cullis, P. R. et al. Role of Drug Delivery Technologies in the Success of COVID-19 Vaccines: A Perspective. Drug Deliv. Transl. Res. 2022, 12 (11), 2581-2588. DOI: 10.1007/s13346-022-01146-1
7. Jiang, D.; Lee, H.; Pardridge, W. M. Plasmid DNA Gene Therapy of the Niemann-Pick C1 Mouse with Transferrin Receptor-Targeted Trojan Horse Liposomes. Sci. Rep. 2020, 10 (1), 13334. DOI: 10.1038/s41598-020-70290-w
8. Sela, M.; Poley, M.; Mora-Raimundo, P. et al. Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease. Adv. Mater. 2023, 35 (51), e2304654. DOI: 10.1002/adma.202304654
9. Fan, K.; Jia, X.; Zhou, M. et al. Ferritin Nanocarrier Traverses the Blood Brain Barrier and Kills Glioma. ACS Nano. 2018, 12 (5), 4105-4115. DOI: 10.1021/acsnano.7b06969
10. Huang, C. W.; Chuang, C. P.; Chen, Y. J. et al. Integrin α₂β₁-Targeting Ferritin Nanocarrier Traverses the Blood-Brain Barrier for Effective Glioma Chemotherapy. J. Nanobiotechnology 2021, 19 (1), 180. DOI: 10.1186/s12951-021-00925-1
11. Karunakaran, I.; van Echten-Deckert, G. Sphingosine 1-Phosphate - A Double Edged Sword in the Brain. Biochim. Biophys. Acta Biomembr. 2017, 1859 (9 Pt B), 1573-1582. DOI: 10.1016/j.bbamem.2017.03.008
12. Pizzo, M. E.; Plowey, E. D.; Khoury, N. et al. Transferrin Receptor-Targeted Anti-Amyloid Antibody Enhances Brain Delivery and Mitigates ARIA. Science 2025, 389 (6760), eads3204. DOI: 10.1126/science.ads3204