Nanoparticle delivery of a prodrug-activating bacterial enzyme leads to anti-tumor responses

Sebastian G. Huayamares, Liming Lian, Regina Rab, Yuning Hou, Afsane Radmand, Hyejin Kim, Ryan Zenhausern, Bhagelu R. Achyut, Melissa Gilbert Ross, Melissa P. Lokugamage, David Loughrey, Hannah E. Peck, Elisa Schrader Echeverri, Alejandro J. Silva Sanchez, Aram Shajii, Andrea Li, Karen E. Tiegreen, Philip J. Santangelo, Eric J. Sorscher () and James E. Dahlman ()
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Sebastian G. Huayamares: Georgia Institute of Technology and Emory University School of Medicine
Liming Lian: Georgia Institute of Technology and Emory University School of Medicine
Regina Rab: Emory University
Yuning Hou: Emory University
Afsane Radmand: Georgia Institute of Technology
Hyejin Kim: Georgia Institute of Technology and Emory University School of Medicine
Ryan Zenhausern: Georgia Institute of Technology and Emory University School of Medicine
Bhagelu R. Achyut: Emory University
Melissa Gilbert Ross: Emory University
Melissa P. Lokugamage: Georgia Institute of Technology and Emory University School of Medicine
David Loughrey: Georgia Institute of Technology and Emory University School of Medicine
Hannah E. Peck: Georgia Institute of Technology and Emory University School of Medicine
Elisa Schrader Echeverri: Georgia Institute of Technology and Emory University School of Medicine
Alejandro J. Silva Sanchez: Georgia Institute of Technology
Aram Shajii: Georgia Institute of Technology and Emory University School of Medicine
Andrea Li: Georgia Institute of Technology and Emory University School of Medicine
Karen E. Tiegreen: Georgia Institute of Technology and Emory University School of Medicine
Philip J. Santangelo: Georgia Institute of Technology and Emory University School of Medicine
Eric J. Sorscher: Emory University
James E. Dahlman: Georgia Institute of Technology and Emory University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Most cancer patients diagnosed with late-stage head and neck squamous cell carcinoma are treated with chemoradiotherapy, which can lead to toxicity. One potential alternative is tumor-limited conversion of a prodrug into its cytotoxic form. We reason this could be achieved by transient and tumor-specific expression of purine nucleoside phosphorylase (PNP), an Escherichia coli enzyme that converts fludarabine into 2-fluoroadenine, a potent cytotoxic drug. To efficiently express bacterial PNP in tumors, we evaluate 44 chemically distinct lipid nanoparticles (LNPs) using species-agnostic DNA barcoding in tumor-bearing mice. Our lead LNP, designated LNP intratumoral (LNPIT), delivers mRNA that leads to PNP expression in vivo. Additionally, in tumor cells transfected with LNPIT, we observe upregulated pathways related to RNA and protein metabolism, providing insight into the tumor cell response to LNPs in vivo. When mice are treated with LNPIT-PNP, then subsequently given fludarabine phosphate, we observe anti-tumor responses. These data are consistent with an approach in which LNP-mRNA expression of a bacterial enzyme activates a prodrug in solid tumors.

Date: 2025
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DOI: 10.1038/s41467-025-58548-1

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