2. Academic Validation
  3. Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy

Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy

  • Nat Nanotechnol. 2026 Mar;21(3):430-442. doi: 10.1038/s41565-025-02102-z.
Qiangqiang Shi # 1,  Ningqiang Gong # 1 2,  Jinjin Wang 1,  Rohan Palanki 1,  Qiuxian Zheng 3,  Mohamad-Gabriel Alameh 4,  Garima Dwivedi 4,  Benjamin Davis 4,  Jilian Melamed 4,  Zhangyi Luo 1,  Junchao Xu 1,  Christian G Figueroa-Espada 1,  Lulu Xue 1,  Ye Zeng 1,  Xuexiang Han 1,  Dongyoon Kim 1,  Qinyuan Chen 5,  Hannah Yamagata 1,  Hannah C Geisler 1,  Rakan El-Mayta 4,  Il-Chul Yoon 1,  Drew Weissman 4 6,  Michael J Mitchell 7 8 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Hefei National Research Center for Physical Science at Microscale, University of Science and Technology of China, Hefei, China.
  • 3 Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 8 Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 9 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 10 Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 11 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • 12 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mjmitch@seas.upenn.edu.
  • # Contributed equally.
PMID: 41851499 DOI: 10.1038/s41565-025-02102-z
Abstract

Regulating T cell phenotypes between activation and exhaustion remains a significant challenge for messenger RNA-based Cancer Immunotherapy. A potential approach to improve anti-cancer T cell activity is to co-deliver interleukin-12 (IL-12), to stimulate effector T cells, and indoleamine 2,3-dioxygenase (IDO) inhibitor, to suppress T cell exhaustion. Here we design prodrug ionizable lipid nanoparticles (pLNPs), via a library of prodrug ionizable lipids (pILs), incorporating an intracellularly cleavable IDO Inhibitor within the pIL structure and encapsulating IL-12 messenger RNA. The lead pIL shows enhanced mRNA transfection over a clinically utilized ionizable lipid, as well as strong immunomodulatory effects via release of the IDO Inhibitor. In a subcutaneous colon Cancer mouse model, pLNP drives complete regression of primary tumours by eliciting effector T cell infiltration while reducing exhaustion, induces a memory T cell response and stimulates a systemic immune response that allows for regression of distal tumours in this study. These results highlight the promise of pLNPs for small-molecule drug and mRNA combination Cancer Immunotherapy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z