Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA
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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a well-characterized tumour-suppressor gene that is lost or mutated in about half of metastatic castration-resistant prostate cancers and in many other human cancers. The restoration of functional PTEN as a treatment for prostate cancer has, however, proven difficult. Here, we show that PTEN messenger RNA (mRNA) can be reintroduced into PTEN-null prostate cancer cells in vitro and in vivo via its encapsulation in polymer-lipid hybrid nanoparticles coated with a polyethylene glycol shell. The nanoparticles are stable in serum, elicit low toxicity and enable high PTEN mRNA transfection in prostate cancer cells. Moreover, significant inhibition of tumour growth is achieved when delivered systemically in multiple mouse models of prostate cancer. We also show that the restoration of PTEN function in PTEN-null prostate cancer cells inhibits the phosphatidylinositol 3-kinase (PI3K)-AKT pathway and enhances apoptosis. Our findings provide proof-of-principle evidence of the restoration of mRNA-based tumour suppression in vivo.
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Regulation of other tumour-associated genes, such as PLK1, Bax, Maspin, PUMA and PTEN, can delay tumour growth in vivo.
“Similarly, the regulation of other tumour-associated genes, such as PLK1 (ref.133), Bax219, Maspin37, PUMA70 and PTEN220, can delay tumour growth in vivo.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [220]
Different non-viral materials have been designed and optimized for accommodating efficient delivery of diverse RNA molecules as well as multi-component genome editing systems.
“Different non-viral materials have been designed and optimized for accommodating efficient delivery of diverse RNA molecules as well as multi-component genome editing systems.[22, 34–36]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [35]
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Self-citation
- Authors
- Islam, M. A., Xu, Y., Tao, W., Ubellacker, J. M., Lim, M., Aum, D., Lee, G. Y., Zhou, K., Zope, H., Yu, M., Cao, W., Oswald, J. T., Dinarvand, M., Mahmoudi, M., Langer, R., Kantoff, P. W., Farokhzad, O. C., Zetter, B. R., & Shi, J.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Farokhzad, Omid C.
- Zetter, Bruce R.
- Shi, Jinjun
- ORCID
- Venue
- Nature Biomedical Engineering
- Published
- 2018-09-17
- Volume
- 2
- Issue
- 11
- Pages
- 850-864
- ISSN
- 2157-846X (ISSN-L)
- PMC
- PMC6486184
- OpenAlex
- W2890364568
- Cited by
- 339
- References
- 78
- Citations by year
- 2026: 22 · 2025: 53 · 2024: 46 · 2023: 66 · 2022: 48 · 2021: 53 · 2020: 38 · 2019: 12 · 2012: 1
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Prostate Cancer Foundation
- National Research Foundation
- National Research Foundation of Korea (K1A1A2048701)
- National Institutes of Health (W81XWH)
- National Heart, Lung, and Blood Institute (R01HL127464)
- National Cancer Institute (R00CA160350, P30CA008748, R01CA200900)
- DOD Prostate Cancer Research Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- PTEN, mRNA delivery, lipid-polymer hybrid nanoparticles, polyethylene glycol coating, castration-resistant prostate cancer, PI3K/Akt signaling, apoptosis, tumor growth inhibition
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Disease Models, Animal, Humans, Lipids, Male, Mice, Inbred BALB C, Mice, Nude, Polyethylene Glycols, Prostatic Neoplasms, RNA, Messenger, Tissue Distribution, Transfection, Signal Transduction, Apoptosis, Phosphatidylinositol 3-Kinases, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Nanoparticles
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