Infectious diseases remain one of the leading causes of death worldwide. Vaccination is a powerful instrument to avert a variety of those by inducing a pathogen-specific immune response and ensure a long-lasting protection against the respective
infection. Nevertheless, due to increasing numbers of immunocompromised patients and emergence of more aggressive pathogens existing vaccination techniques are limited. In our study we investigated a new strategy to strengthen
vaccine adjuvant in order to increase immunity against
infectious diseases. The strategy is based on an amplification of
Toll-like receptor 4 (TLR4) -induced activation of antigen-presenting cells (APCs) by turning off a powerful endogenous inhibitor of APC-activation. TLR4 signaling induces the release of
cytokines that bind autocrine and paracrine to receptors, activating the
Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 3 cascade. Subsequently, STAT3 induces expression of suppressor of
cytokine signaling (SOCS) 1 that terminates the inflammatory response. In the approach, TLR4-adjuvant
monophosphoryl lipid A (MPLA)-stimulated monocyte-activation is reinforced and sustained by silencing SOCS1 via
lipid nanoparticle-enclosed
siRNA (L-
siRNA). L-
siRNA is transported into primary cells without any toxic side effects and protected from early degradation. Through
lipid core-embedded functional groups the
lipid particle escapes from endosomes and releases the
siRNA when translocated into the cytoplasm. SOCS1 is potently silenced, and SOCS1-mediated termination of NFκB signaling is abrogated. Consequently, the MPLA-stimulated activation of APCs, monitored by release of pro-inflammatory
cytokines such as
IL-6, TNFα, and IL-1β, upregulation of
MHC class II molecules and costimulatory CD80/CD86 is strongly enhanced and prolonged. SOCS1-silenced APCs, pulsed with liposomal
tetanus light chain toxin (TeTxLC)
antigen, activate autologous T cells much more intensively than SOCS1-expressing cells. Importantly, expansion of cocultured CD4+ as well as CD8+ T cells is remarkably enhanced. Furthermore, our results point toward a broad T helper cell response as TH1 typical as well as TH2 characteristic
cytokines are elevated. Taken together, this study in the human system comprises a translational potential to develop more effective
vaccines against
infectious diseases by inhibition of the endogenous negative-feedback loop in APCs.