Predictive High-Throughput Platform for Dual Screening of mRNA Lipid Nanoparticle Blood–Brain Barrier Transfection and Crossing

Han, Emily L.; Padilla, Marshall S.; Palanki, Rohan; Kim, Dongyoon; Mrksich, Kaitlin; Li, Jacqueline J.; Tang, Sophia; Yoon, Il-Chul; Mitchell, Michael J.

doi:10.1021/acs.nanolett.3c03509

Cited by 17 publications

(3 citation statements)

References 49 publications

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“…The results of the last few years emphasized by the extraordinary outputs recorded after the worldwide administration of mRNA anti-COVID vaccines, confirm that the therapeutic potential of LNPs, combined with RNA technologies, will reach outstanding result in cancer gene therapy, including neurological and skin cancers [175][176][177][178].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 85%

Lipid nanoparticles-based RNA therapies for breast cancer treatment

Serpico,

Zhu,

Maia

et al. 2024

Drug Deliv. and Transl. Res.

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Breast cancer (BC) prevails as a major burden on global healthcare, being the most prevalent form of cancer among women. BC is a complex and heterogeneous disease, and current therapies, such as chemotherapy and radiotherapy, frequently fall short in providing effective solutions. These treatments fail to mitigate the risk of cancer recurrence and cause severe side effects that, in turn, compromise therapeutic responses in patients. Over the last decade, several strategies have been proposed to overcome these limitations. Among them, RNA-based technologies have demonstrated their potential across various clinical applications, notably in cancer therapy. However, RNA therapies are still limited by a series of critical issues like off-target effect and poor stability in circulation. Thus, novel approaches have been investigated to improve the targeting and bioavailability of RNA-based formulations to achieve an appropriate therapeutic outcome. Lipid nanoparticles (LNPs) have been largely proven to be an advantageous carrier for nucleic acids and RNA. This perspective explores the most recent advances on RNA-based technology with an emphasis on LNPs’ utilization as effective nanocarriers in BC therapy and most recent progresses in their clinical applications. Graphical Abstract

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Section: Conclusion and Future Perspectivesmentioning

confidence: 85%

Lipid nanoparticles-based RNA therapies for breast cancer treatment

Serpico,

Zhu,

Maia

et al. 2024

Drug Deliv. and Transl. Res.

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“…Indeed, in this light, advances in lipid nanoparticle-mediated mRNA therapeutics are particularly exciting as they provide a mechanism to introduce a transient dose of Hsp104 variants to where they are needed. 81,82 In this way, potentiated Hsp104 variants could relieve toxic protein aggregation and then be downregulated such that potential off-target effects are minimized.…”

Section: Discussionmentioning

confidence: 99%

Design principles to tailor Hsp104 therapeutics

Lin,

Carman,

Gambogi

et al. 2024

Preprint

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The hexameric AAA+ disaggregase, Hsp104, collaborates with Hsp70 and Hsp40 via its autoregulatory middle domain (MD) to solubilize aggregated protein conformers. However, how ATP- or ADP-specific MD configurations regulate Hsp104 hexamers remains poorly understood. Here, we define an ATP-specific network of interprotomer contacts between nucleotide-binding domain 1 (NBD1) and MD helix L1, which tunes Hsp70 collaboration. Manipulating this network can: (a) reduce Hsp70 collaboration without enhancing activity; (b) generate Hsp104 hypomorphs that collaborate selectively with class B Hsp40s; (c) produce Hsp70-independent potentiated variants; or (d) create species barriers between Hsp104 and Hsp70. Conversely, ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity, and their perturbation frequently potentiates Hsp104. Importantly, adjusting the NBD1:MD helix L1 rheostat via rational design enables finely tuned collaboration with Hsp70 to safely potentiate Hsp104, minimize off-target toxicity, and counteract FUS proteinopathy in human cells. Thus, we establish important design principles to tailor Hsp104 therapeutics.

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“…This could potentially be a promising start for the application of precision LNPs to target the brain. Han et al, 2023, for their development of a high-throughput screening platform (HTS-BBB) for the dual screening of mRNA LNP transfection of and transport across the BBB, developed strains of LNPs that reportedly crossed the BBB in their mouse model and reached the brain [197]. To date, only one study has successfully packaged the PE system into lipid nanoparticles (LNPs) by delivering PE mRNA and chemical-engineered pegRNA for in vivo treatment.…”

Section: Cationic Lipid-based Nanoparticlesmentioning

confidence: 99%

Emerging Perspectives on Prime Editor Delivery to the Brain

BenDavid,

Ramezanian,

et al. 2024

Pharmaceuticals

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Prime editing shows potential as a precision genome editing technology, as well as the potential to advance the development of next-generation nanomedicine for addressing neurological disorders. However, turning in prime editors (PEs), which are macromolecular complexes composed of CRISPR/Cas9 nickase fused with a reverse transcriptase and a prime editing guide RNA (pegRNA), to the brain remains a considerable challenge due to physiological obstacles, including the blood–brain barrier (BBB). This review article offers an up-to-date overview and perspective on the latest technologies and strategies for the precision delivery of PEs to the brain and passage through blood barriers. Furthermore, it delves into the scientific significance and possible therapeutic applications of prime editing in conditions related to neurological diseases. It is targeted at clinicians and clinical researchers working on advancing precision nanomedicine for neuropathologies.

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Predictive High-Throughput Platform for Dual Screening of mRNA Lipid Nanoparticle Blood–Brain Barrier Transfection and Crossing

Cited by 17 publications

References 49 publications

Lipid nanoparticles-based RNA therapies for breast cancer treatment

Lipid nanoparticles-based RNA therapies for breast cancer treatment

Design principles to tailor Hsp104 therapeutics

Emerging Perspectives on Prime Editor Delivery to the Brain

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