Recently, Zhang Feng's team from the Broad Institute published a research paper titled "Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery" online in PNAS. The study systematically explored human PNMA proteins and found that human cells secrete many PNMAs.
The study determined that PNMA2 efficiently forms icosahedral capsids but does not naturally encapsulate nucleic acids. This study resolved the cryo-electron microscopy (cryo-EM) structure of PNMA2 and used the structure to design engineered PNMA2 (ePNMA2) particles with RNA packaging capabilities. Recombinantly purified ePNMA2 protein packages mRNA molecules into icosahedral capsids and can serve as a delivery vehicle in mammalian cell lines, demonstrating the potential of engineered endogenous capsids as a delivery modality for nucleic acid therapeutics.
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RNA-based therapeutics, including mRNA-based vaccines, have the potential to be widely used in a variety of disease settings. To realize this potential, we need a set of delivery vehicles that can effectively package and safely deliver therapeutic RNA cargo to specific tissues. Several delivery modalities have been developed, including non-viral methods such as lipid nanoparticles (LNPs), which have been successfully used to deliver oligonucleotide and mRNA therapeutics, and viral vectors such as adeno-associated viruses (AAV). However, the broad applicability of these approaches is limited by factors such as cargo size limitations, immunogenicity, difficulty in achieving tissue-specific targeting, and scalable production.
Natural delivery systems derived from the human genome may provide the basis for new engineered gene transfer modalities that could address these limitations. Recent studies have found that there are multiple endogenous gag-like genes in the human genome, which are similar to retroviral structural proteins and therefore may be designed for gene transfer. Some of these genes, including Arc and Peg10, have been domesticated and play important roles in normal mammalian physiology. Previous studies have also shown that ARC and PEG10 gag-like proteins have the ability to form capsid structures that can package their cognate mRNAs. To extend this natural ability, PEG10 was recently designed to programmably package and deliver exogenous cargo, mRNA, into human cells. The potential of these endogenous retrotransposon-derived proteins as a novel nucleic acid delivery modality is demonstrated.
To further explore the potential of endogenous gag-like proteins for therapeutic RNA delivery, researchers sought to systematically characterize the paraneoplastic Ma antigen (PNMA) protein family. It contains more than 12 proteins in humans and was originally discovered due to the fact that some PNMAs encode autoantigens in patients with paraneoplastic neurological diseases. Although some PNMA family members have been previously reported to play a role in apoptosis, most remain poorly characterized. However, some PNMAs, including mouse PNMA2, have been shown to form capsid structures, suggesting that they may be suitable as delivery vehicles.
Figure 1. Cryo-EM structure of human PNMA2 capsids. (Madigan V, et al., 2024)
The study explored the potential of human PNMA proteins to form capsids and package RNA. The study found that PNMA2 is abundantly secreted from human cells as an icosahedral capsid and can self-assemble recombinant proteins in vitro. This study used cryo-electron microscopy (cryo-EM) to analyze the structure of the PNMA2 protein capsid, and used structure-guided engineering to modify the PNMA2 protein capsid to package mRNA. These engineered PNMA2 capsids were found to functionally deliver mRNA into recipient cells, demonstrating their promise as a therapeutic mRNA delivery vehicle. In addition to PNMA2, the study found that other PNMA family members are also capable of forming virus-like capsids, suggesting that they may also be suitable for delivery and raising the possibility that these proteins are involved in cell-to-cell communication.
Reference
Madigan V, et al. Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery. Proceedings of the National Academy of Sciences, 2024, 121(11): e2307812120.