Nanoadjuvant‐Mediated EV‐Derived Artificial APC to Trigger Protective Immunity Against Virus Infection

Abstract Antigen presentation is a crucial process for vaccine‐induced immunity, as it determines the efficiency of a vaccine in eliciting effective antigen‐specific immune responses by simultaneously processing antigens and presenting them to T cells. A nano‐APC is designed and proposed to bypass the antigen processing step by antigen‐presenting cells (APCs) in vivo, directly eliciting effective antigen‐specific cellular immunity to protect against lethal viral infections. Extracellular vesicles (EVs) equipped with essential moieties for antigen presentation are prepared by incubating antigen‐loaded self‐adjuvanting chitosan nanoparticles (nChi) with naïve APCs. nChi enhances antigen uptake, activates stimulatory factors, and promotes EV production. Remarkably, the EVs generated after APC activation by nChi retain key characteristics of the source cells, enabling them to effectively stimulate specific T cell proliferation in vitro, thereby acting as nano‐antigen‐presenting cells (nano‐APCs). Due to direct T cell activation, nano‐APC vaccines trigger a rapid and long‐lasting antigen‐specific humoral immunity and strong cellular immunity upon vaccination. In a 50‐fold LD50 influenza virus challenge, nano‐APC vaccines significantly enhanced mouse survival compared to the nanoparticle‐based vaccination group and other controls. These results suggest that nChi‐promoted EVs enable direct antigen presentation to T cells, paving the way for the development of an effective, safe, and versatile EV‐based vaccine platform.