Biomimetic Exosome‐Camouflaged pH‐Responsive Dendrimer Nanogels as a Therapeutic Vaccine Against Pancreatic Cancer Through Reprogramming of Multiple Cell Types

ABSTRACT Cancer vaccines suffer limitations by inefficient antigen cross‐presentation, immunosuppressive tumor microenvironment (TME), and lack of efficient reprogramming of multiple cell types (cancer cells, macrophages, and dendritic cells). Herein, we develop exosome (Exo)‐coated pH‐sensitive dendrimer nanogels (DNGs) as a potent therapeutic cancer nanovaccine through multiple modulation of cancer cells, macrophages, and dendritic cells. DNGs were first prepared through a reverse‐phase microemulsion technique using toyocamycin (Toy)‐conjugated generation 3 poly(amidoamine) dendrimers as monomers and terephthalaldehyde‐polyethylene glycol‐benzaldehyde as a crosslinker, in‐situ loaded with gold nanoparticles (Au NPs), physically loaded with an immune adjuvant CpG, and lastly coated with cancer cell‐derived Exos. The formed Au‐DNGs/CpG@Exo have a size of 111.6 nm and pH‐responsive Toy release property under a TME‐mimetic environment. The nanovaccine enables homologous tumor targeting delivery of Toy to mediate chemotherapy for immunogenic cell death (ICD) induction, and delivery of adjuvant/Exo‐derived antigens to dendritic cells for triple ICD‐, adjuvant‐ and antigen‐mediated maturation. Meanwhile, the loaded Au NPs remodel the immunosuppressive microenvironment through macrophage M1 repolarization/lysosomal dysfunction to boost immune activation. Such biomimetic DNGs enable effective tumor inhibition and recurrence prevention in a pancreatic tumor mouse model, and may be developed as a therapeutic nanovaccine to tackle other cancer types through reprogramming of multiple cells.