mRNA lipid nanoparticle-incorporated nanofiber-hydrogel composite generates a local immunostimulatory niche for cancer immunotherapy

Zhu, Y.; Yao, Z.-C.; Li, S.; Ma, J.; Wei, C.; Yu, D.; Stelzel, J. L.; Ni, B. Y. X.; Miao, Y.; Van Batavia, K.; Lu, X.; Lin, J.; Dai, Y.; Kong, J.; Shen, R.; Goodier, K. D.; Liu, X.; Cheng, L.; Vuong, I.; Howard, G. P.; Livingston, N. K.; Choy, J.; Schneck, J. P.; Doloff, J. C.; Reddy, S. K.; Hickey, J. W.; Mao, H.-Q.

doi:10.1101/2025.01.27.633179

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bioRxiv · 10.1101/2025.01.27.633179

mRNA lipid nanoparticle-incorporated nanofiber-hydrogel composite generates a local immunostimulatory niche for cancer immunotherapy

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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 potent transfection efficiency of LNPs in antigen-presenting cells (APCs), LiNx demonstrates remarkable immune cell recruitment, antigen expression and presentation, and cellular interaction. These attributes collectively create an immunostimulating milieu and yield a potent immune response achievable with a single dose, comparable to the conventional three-dose LNP immunization regimen. Further investigations reveal that the LiNx not only generates heightened Th1 and Th2 responses but also elicits a distinctive Type 17 T helper cell-mediated response pivotal for bolstering antitumour efficacy. Our findings elucidate the mechanism underlying LiNxs role in potentiating antigen-specific immune responses, presenting a new strategy for cancer immunotherapy.

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Zhu, Y., Yao, Z.-C., Li, S., Ma, J., Wei, C., Yu, D., Stelzel, J. L., Ni, B. Y. X., Miao, Y., Van Batavia, K., Lu, X., Lin, J., Dai, Y., Kong, J., Shen, R., Goodier, K. D., Liu, X., Cheng, L., Vuong, I., Howard, G. P., Livingston, N. K., Choy, J., Schneck, J. P., Doloff, J. C., Reddy, S. K., Hickey, J. W., Mao, H.-Q.. 2025-01-29. mRNA lipid nanoparticle-incorporated nanofiber-hydrogel composite generates a local immunostimulatory niche for cancer immunotherapy. https://doi.org/10.1101/2025.01.27.633179

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