PMID- 38437549 OWN - NLM STAT- MEDLINE DCOM- 20240306 LR - 20240320 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 121 IP - 11 DP - 2024 Mar 12 TI - Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery. PG - e2307812120 LID - 10.1073/pnas.2307812120 [doi] LID - e2307812120 AB - A number of endogenous genes in the human genome encode retroviral gag-like proteins, which were domesticated from ancient retroelements. The paraneoplastic Ma antigen (PNMA) family members encode a gag-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. FAU - Madigan, Victoria AU - Madigan V AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Zhang, Yugang AU - Zhang Y AUID- ORCID: 0000-0002-1141-5821 AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Raghavan, Rumya AU - Raghavan R AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Wilkinson, Max E AU - Wilkinson ME AUID- ORCID: 0000-0003-4738-9503 AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Faure, Guilhem AU - Faure G AUID- ORCID: 0000-0001-9537-2277 AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Puccio, Elena AU - Puccio E AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Segel, Michael AU - Segel M AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Lash, Blake AU - Lash B AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Macrae, Rhiannon K AU - Macrae RK AUID- ORCID: 0000-0002-7850-9056 AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. FAU - Zhang, Feng AU - Zhang F AUID- ORCID: 0000-0002-7444-1103 AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142. AD - McGovern Institute for Brain Research at Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - HHMI, Cambridge, MA 02139. LA - eng GR - F31 CA275339/CA/NCI NIH HHS/United States GR - F32 AI161868/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20240304 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Ma2 antigen) RN - 0 (RNA, Messenger) RN - 0 (Nerve Tissue Proteins) RN - 0 (Antigens, Neoplasm) SB - IM MH - Animals MH - Humans MH - RNA, Messenger/genetics MH - *Capsid MH - Cryoelectron Microscopy MH - *Nerve Tissue Proteins MH - Mammals MH - *Antigens, Neoplasm PMC - PMC10945824 OTO - NOTNLM OT - PNMA OT - VLP OT - capsid OT - gene therapy OT - mRNA delivery COIS- Competing interests statement:The authors declare no competing interest. EDAT- 2024/03/04 18:42 MHDA- 2024/03/06 06:43 PMCR- 2024/03/04 CRDT- 2024/03/04 15:23 PHST- 2024/03/06 06:43 [medline] PHST- 2024/03/04 18:42 [pubmed] PHST- 2024/03/04 15:23 [entrez] PHST- 2024/03/04 00:00 [pmc-release] AID - 202307812 [pii] AID - 10.1073/pnas.2307812120 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2024 Mar 12;121(11):e2307812120. doi: 10.1073/pnas.2307812120. Epub 2024 Mar 4.