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

Author

Listed:
  • 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
    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
    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
    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
    Emory University)

  • James E. Dahlman

    (Georgia Institute of Technology and Emory University School of Medicine)

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.

Suggested Citation

  • 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 & Ha, 2025. "Nanoparticle delivery of a prodrug-activating bacterial enzyme leads to anti-tumor responses," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58548-1
    DOI: 10.1038/s41467-025-58548-1
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    References listed on IDEAS

    as
    1. Huanzhen Ni & Marine Z. C. Hatit & Kun Zhao & David Loughrey & Melissa P. Lokugamage & Hannah E. Peck & Ada Del Cid & Abinaya Muralidharan & YongTae Kim & Philip J. Santangelo & James E. Dahlman, 2022. "Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Pooja Munnilal Tiwari & Daryll Vanover & Kevin E. Lindsay & Swapnil Subhash Bawage & Jonathan L. Kirschman & Sushma Bhosle & Aaron W. Lifland & Chiara Zurla & Philip J. Santangelo, 2018. "Engineered mRNA-expressed antibodies prevent respiratory syncytial virus infection," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    3. Siddharth Patel & N. Ashwanikumar & Ema Robinson & Yan Xia & Cosmin Mihai & Joseph P. Griffith & Shangguo Hou & Adam A. Esposito & Tatiana Ketova & Kevin Welsher & John L. Joyal & Örn Almarsson & Gaur, 2020. "Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Siddharth Patel & N. Ashwanikumar & Ema Robinson & Yan Xia & Cosmin Mihai & Joseph P. Griffith & Shangguo Hou & Adam A. Esposito & Tatiana Ketova & Kevin Welsher & John L. Joyal & Örn Almarsson & Gaur, 2020. "Author Correction: Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
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