Overcoming Challenges in Dengue Vaccine Development: Advanced Delivery Approaches.

Dengue virus (DENV), comprising four antigenically distinct serotypes, remains a major global health problem. Vaccine development is hindered by immunological barriers, including antibody-dependent enhancement (ADE), original antigenic sin, and the requirement for balanced, long-lasting immunity against all serotypes. This review focuses on emerging strategies that improve vaccine-induced immune memory through rational antigen design and advanced delivery systems. Nanoparticles, including lipid-based carriers, polymeric particles, and virus-like particles (VLPs), support antigen stability, promote dendritic cell (DC) uptake, and enhance delivery to the lymph node. Injectable hydrogels and responsive biomaterials provide sustained antigen release, promoting germinal center (GC) formation and memory B and T-cell memory responses. Targeted delivery using ligands for C-type lectins or mannose receptors further increases the antigen presentation efficiency. Potent adjuvants, including toll- like receptor (TLR) agonists (Poly I:C, CpG, and R848) and saponin-based molecules (QS-21, MPL), activate innate immune sensors and guide Th1-type adaptive responses. New vaccine formulations, including multiepitope peptide vaccines, mRNA and DNA constructs, and extracellular vesicle (EV)-based carriers derived from DCs or milk, offer cell-free, scalable, and immune system-activating platforms. Furthermore, in silico approaches facilitate epitope identification, MHC-binding prediction, and immune response simulation. Collectively, these strategies address recent challenges and support the development of dengue vaccines that offer enhanced safety and durable immunity.