An mRNA lipid nanoparticle-incorporated nanofiber-hydrogel composite for cancer immunotherapy

Yining Zhu, Zhi-Cheng Yao, Shuyi Li, Jingyao Ma, Christine Wei, Di Yu, Jessica L. Stelzel, Bobby Y. X. Ni, Yang Miao, Kyra Van Batavia, Xiaoya Lu, Jinghan Lin, Yifan Dai, Jiayuan Kong, Ruochen Shen, Kailei D. Goodier, Xiang Liu, Leonardo Cheng, Ivan Vuong, Gregory P. Howard, Natalie K. Livingston, Joseph Choy, Jonathan P. Schneck, Joshua C. Doloff, Sashank K. Reddy, John W. Hickey and Hai-Quan Mao ()
Additional contact information
Yining Zhu: Johns Hopkins University School of Medicine
Zhi-Cheng Yao: Johns Hopkins University
Shuyi Li: Johns Hopkins University
Jingyao Ma: Johns Hopkins University
Christine Wei: Johns Hopkins University School of Medicine
Di Yu: Johns Hopkins University School of Medicine
Jessica L. Stelzel: Johns Hopkins University School of Medicine
Bobby Y. X. Ni: Duke University
Yang Miao: Duke University
Kyra Van Batavia: Duke University
Xiaoya Lu: Johns Hopkins University
Jinghan Lin: Johns Hopkins University
Yifan Dai: University of North Carolina at Chapel Hill
Jiayuan Kong: Johns Hopkins University
Ruochen Shen: Johns Hopkins University School of Medicine
Kailei D. Goodier: Johns Hopkins University
Xiang Liu: Johns Hopkins University
Leonardo Cheng: Johns Hopkins University School of Medicine
Ivan Vuong: Johns Hopkins University School of Medicine
Gregory P. Howard: Johns Hopkins University School of Medicine
Natalie K. Livingston: Johns Hopkins University School of Medicine
Joseph Choy: Johns Hopkins University
Jonathan P. Schneck: Johns Hopkins University
Joshua C. Doloff: Johns Hopkins University School of Medicine
Sashank K. Reddy: Johns Hopkins University School of Medicine
John W. Hickey: Duke University
Hai-Quan Mao: Johns Hopkins University School of Medicine

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

Abstract: Abstract Hydrogel materials have emerged as versatile platforms for various biomedical applications. Notably, the engineered nanofiber-hydrogel composite (NHC) has proven effective in mimicking the soft tissue extracellular matrix, facilitating substantial recruitment of host immune cells and the formation of a local immunostimulatory microenvironment. Leveraging this feature, here we report an mRNA lipid nanoparticle (LNP)-incorporated NHC microgel matrix, termed LiNx, by incorporating LNPs loaded with mRNA encoding tumour antigens. Harnessing the high transfection efficiency of LNPs in antigen-presenting cells, LiNx demonstrates substantial levels of immune cell recruitment, antigen expression and presentation, and cellular interaction. These attributes collectively create an immunostimulating microenvironment and yield a potent immune response with a single dose at a level comparable to the conventional three-dose LNP immunization protocol. Further investigation reveals that the LiNx generates not only high levels of Th1 and Th2 responses, but also a distinct Type 17 T helper cell response critical for bolstering antitumour efficacy. Our findings elucidate the mechanism underlying LiNx’s role in potentiating antigen-specific immune responses, presenting a strategy for cancer immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-61299-8

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