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

• DOI: 10.1038/s41467-025-58548-1
• Publication Date: 2025-04-12T20:43:30Z
• Authors: Sebastian G. Huay...; Liming Lian; Regina Rab; Yuning Hou; Afsane Radmand; Hyejin Kim; Ryan Zenhausern; Bhagelu R. Achyut; Melissa Gilbert Ross; Melissa P. Lokuga...; David Loughrey; Hannah E. Peck; Elisa Schrader Ec...; Alejandro J. Da S...; Aram Shajii; Andrea Li; Karen E. Tiegreen; Philip J. Santangelo; Eric J. Sorscher; James E. Dahlman

Most cancer patients diagnosed with late-stage head and neck squamous cell carcinoma are treated 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 tumor-specific expression purine nucleoside phosphorylase (PNP), an Escherichia coli enzyme that converts fludarabine 2-fluoroadenine, potent drug. To efficiently express bacterial PNP in tumors, we evaluate 44 chemically distinct lipid nanoparticles (LNPs) using species-agnostic DNA barcoding tumor-bearing mice. Our LNP, designated LNP intratumoral (LNPIT), delivers mRNA leads vivo. Additionally, tumor cells transfected LNPIT, observe upregulated pathways related RNA protein metabolism, providing insight the response LNPs When mice LNPIT-PNP, then subsequently given phosphate, anti-tumor responses. These data consistent approach LNP-mRNA activates solid tumors.