Selenium Nanoadjuvant‐Based Extracellular Vesicle Vaccines With Immunohomeostasis Regulation Properties for Combating Drug‐Resistant Bacteria Infection

ABSTRACT Malfunctions of immune cells induced by drug‐resistant bacterial infections is one of the major challenges in their clinical treatment. Herein, inspired by the crucial roles of selenoproteins in maintaining the immunological functions, we synthesized Se nanoadjuvant‐based extracellular vesicles (EVs) vaccines by directly harvesting EVs from MRSA treated with Se nanoadjuvant, using the EVs secretion property of bacteria under stress. Intriguingly, the Se nanoadjuvant not only significantly facilitated the uptake of EVs into dendritic cells, but also enhanced their abilities to produce multiple cytokines by triggering TLR2 signaling pathways and regulating the expression of selenoproteins to relieve ROS generation within immune cells. Meanwhile, Se nanoadjuvant‐based EVs vaccines also significantly enhanced the immunogenicity of EVs to induce the multifunctionality and proliferation of T lymphocytes, more follicular helper T cells, long‐lived plasma cells, and robust generation of antibodies with high titers. These advantages endowed nanovaccines with high activity for eliminating MRSA at the early stage. Furthermore, nanovaccines could reshape immune homeostasis at the late stage to facilitate wound repair, which may be attributed to their regulations of multiple selenoprotein expressions to modulate the immune microenvironment within the wound. This study describes a unique nanoadjuvant for the development of EV‐based bacterial vaccines.