Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery

A number of endogenous genes in the human genome encode retroviral -like proteins, which were domesticated from ancient retroelements. The paraneoplastic Ma antigen (PNMA) family members encode a -like capsid domain, but their ability to assemble as capsids and traffic between cells remains mostly u...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2024-03, Vol.121 (11), p.e2307812120-e2307812120
Main Authors: Madigan, Victoria, Zhang, Yugang, Raghavan, Rumya, Wilkinson, Max E, Faure, Guilhem, Puccio, Elena, Segel, Michael, Lash, Blake, Macrae, Rhiannon K, Zhang, Feng
Format: Article
Language:English
Subjects:
Animals
Antigens
Antigens, Neoplasm
Biological Sciences
Capsid
Capsids
Cell lines
Cryoelectron Microscopy
Genomes
Humans
Mammals
mRNA
Nerve Tissue Proteins
Nucleic acids
Proteins
RNA, Messenger - genetics
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Summary:A number of endogenous genes in the human genome encode retroviral -like proteins, which were domesticated from ancient retroelements. The paraneoplastic Ma antigen (PNMA) family members encode a -like capsid domain, but their ability to assemble as capsids and traffic between cells remains mostly uncharacterized. Here, we systematically investigate human PNMA proteins and find that a number of PNMAs are secreted by human cells. We determine that PNMA2 forms icosahedral capsids efficiently but does not naturally encapsidate nucleic acids. We resolve the cryoelectron microscopy (cryo-EM) structure of PNMA2 and leverage the structure to design engineered PNMA2 (ePNMA2) particles with RNA packaging abilities. Recombinantly purified ePNMA2 proteins package mRNA molecules into icosahedral capsids and can function as delivery vehicles in mammalian cell lines, demonstrating the potential for engineered endogenous capsids as a nucleic acid therapy delivery modality.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2307812120