Engineering Tfh-Specific Nanoadjuvant to Counteract Bile Acid-Induced Mitophagy and Vaccine Hyporesponsivenes

Bile acids were involved in vaccine response and modulating immune cells. Follicular helper T (Tfh) cells serve a critical immunoregulatory function in vaccine response. However, the precise role of bile acids in modulating Tfh cells and the underlying mechanisms remain unclear. Nano-adjuvant targeting and modulating Tfh cells may offer a promising strategy to improve vaccine response. In this study, we first discovered that 3-oxo-lithocholic acid (3-oxoLCA) impaired the differentiation and function of cultured Tfh vacells both in human and mice in vitro. In vivo, 3-oxoLCA gavage significantly reduced the proportion of Tfh cells in spleen and antibody responses in WT mice under NP-OVA immunization. Mechanistically, 3-oxoLCA promoted intracellular mitophagy of Tfh cells by RNA sequencing analysis and rescue experiment. Leveraging these insights, we engineered a mitophagy-inhibiting, Tfh cells-targeted nano-adjuvant (M-1@NP) decorated with anti-CXCR5 and anti-ICOS antibodies to precisely increased Tfh cells generation and function. This nanoplatform not only boosted cultured Tfh cells generation in vitro but also amplified germinal center (GC) responses and specific antibody production in immunized mice, with high targeting specificity and biocompatibility. In conclusion, 3-oxoLCA inhibited the differentiation and function of mouse and human Tfh cells by promoting intracellular mitophagy. Tfh cells-targeted nano-adjuvant effectively enhanced the ratio and functions of Tfh cells. M-1@NP represents a potentially valuable option for promoting vaccine response in clinical applications.