Functionalized nanowires for miRNA-mediated therapeutic programming of naïve T cells

• Published in: Nature nanotechnology Vol. 19; no. 8; pp. 1190 - 1202
• Main Authors: Yee Mon, Kristel J., Kim, Sungwoong, Dai, Zhonghao, West, Jessica D., Zhu, Hongya, Jain, Ritika, Grimson, Andrew, Rudd, Brian D., Singh, Ankur
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2024; Nature Publishing Group
• Subjects: 142/126; 631/61/350/2093; 631/61/350/2251; 631/61/54/152; 639/166/985; 639/925/357/1016; Adoptive transfer; Animals; Cationic polymerization; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Differentiation; Cell proliferation; Cell therapy; Chemistry and Materials Science; Clonal deletion; Differentiation (biology); Effectiveness; Effector cells; Gene regulation; Humans; Immunological memory; In vivo methods and tests; Lymphocytes; Lymphocytes T; Materials Science; Memory cells; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; miRNA; Nanotechnology; Nanotechnology and Microengineering; Nanowires; Nanowires - chemistry; Pathogens; Polymers; Programming
• ISSN: 1748-3387; 1748-3395; 1748-3395
• DOI: 10.1038/s41565-024-01649-7

Cellular programming of naïve T cells can improve the efficacy of adoptive T-cell therapy. However, the current ex vivo engineering of T cells requires the pre-activation of T cells, which causes them to lose their naïve state. In this study, cationic-polymer-functionalized nanowires were used to pre-program the fate of primary naïve CD8
+
T cells to achieve a therapeutic response in vivo. This was done by delivering single or multiple microRNAs to primary naïve mouse and human CD8
+
T cells without pre-activation. The use of nanowires further allowed for the delivery of large, whole lentiviral particles with potential for long-term integration. The combination of deletion and overexpression of miR-29 and miR-130 impacted the ex vivo T-cell differentiation fate from the naïve state. The programming of CD8
+
T cells using nanowire-delivered co-delivery of microRNAs resulted in the modulation of T-cell fitness by altering the T-cell proliferation, phenotypic and transcriptional regulation, and secretion of effector molecules. Moreover, the in vivo adoptive transfer of murine CD8
+
T cells programmed through the nanowire-mediated dual delivery of microRNAs provided enhanced immune protection against different types of intracellular pathogen (influenza and
Listeria monocytogenes
). In vivo analyses demonstrated that the simultaneous alteration of miR-29 and miR-130 levels in naïve CD8
+
T cells reduces the persistence of canonical memory T cells whereas increases the population of short-lived effector T cells. Nanowires could potentially be used to modulate CD8
+
T-cell differentiation and achieve a therapeutic response in vivo without the need for pre-activation.
Ex vivo engineering of T cells for adoptive T-cell therapy without pre-activation is challenging and hinders therapeutic efficacy. Here, using nanowires, the delivery of microRNAs to primary naïve mouse and human CD8
+
T cells without pre-activation for immune protection against pathogens is demonstrated.