Nanoparticle delivery of a prodrug-activating bacterial enzyme leads to anti-tumor responses
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 (LNP<sup>IT</sup>), delivers mRNA that leads to PNP expression in vivo. Additionally, in tumor cells transfected with LNP<sup>IT</sup>, 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 LNP<sup>IT</sup>-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.
Authors
- Bhagelu R. Achyut (ORCID: https://orcid.org/0000-0001-5670-6983)
- Afsane Radmand
- Liming Lian (ORCID: https://orcid.org/0000-0002-9249-7768)
- Regina Rab (ORCID: https://orcid.org/0000-0003-0293-4694)
- Philip J. Santangelo (ORCID: https://orcid.org/0000-0001-7352-0339)
- Yuning Hou (ORCID: https://orcid.org/0000-0001-9894-3821)
- Alejandro J. Da Silva Sanchez
- James E. Dahlman (ORCID: https://orcid.org/0000-0001-7580-436X)
- Ryan Zenhausern (ORCID: https://orcid.org/0000-0002-2538-0033)
- Eric J. Sorscher (ORCID: https://orcid.org/0000-0001-9341-3354)
- Melissa Gilbert‐Ross (ORCID: https://orcid.org/0000-0002-1960-8302)
- David Loughrey (ORCID: https://orcid.org/0000-0002-2271-6574)
- Elisa Schrader Echeverri (ORCID: https://orcid.org/0000-0003-4094-2054)
- Sebastian G. Huayamares (ORCID: https://orcid.org/0000-0003-2859-3074)
- Aram Shajii
- Melissa P. Lokugamage (ORCID: https://orcid.org/0000-0001-7064-5021)
- Karen E. Tiegreen (ORCID: https://orcid.org/0009-0001-0620-7753)
- Hyejin Kim (ORCID: https://orcid.org/0000-0002-7937-2733)
- Hannah E. Peck (ORCID: https://orcid.org/0000-0002-2620-5392)
- Andrea Li
Institutions
- Georgia Institute of Technology (US)
- Emory University (US)
- The Wallace H. Coulter Department of Biomedical Engineering (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-12
- DOI
- https://doi.org/10.1038/s41467-025-58548-1
- Citations
- 9
- Primary Topic
- Cancer Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 9.86
Funders
- Georgia Research Alliance
- Frederick National Laboratory for Cancer Research
- National Institutes of Health
- National Cancer Institute