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

• DOI: 10.1073/pnas.2307812120
• Publication Date: 2024-03-04T20:12:57Z
• Authors: Victoria Madigan; Yugang Zhang; Rumya Raghavan; Max E. Wilkinson; Guilhem Faure; Elena Puccio; Michael Segel; Blake Lash; Rhiannon K. Macrae; Feng Zhang
• Keywords: Mammals; 0303 health sciences; 03 medical and health sciences; Capsid; Antigens, Neoplasm; Cryoelectron Microscopy; Animals; Humans; Nerve Tissue Proteins; RNA, Messenger; Biological Sciences

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.