Redox‐Responsive Dendrimer Nanogels Enable Ultrasound‐Enhanced Chemoimmunotherapy of Pancreatic Cancer via Endoplasmic Reticulum Stress Amplification and Macrophage Polarization

Abstract Developing a multifunctional nanoplatform to achieve efficient theranostics of tumors through multi‐pronged strategies remains to be challenging. Here, the design of the intelligent redox‐responsive generation 3 (G3) poly(amidoamine) dendrimer nanogels (NGs) loaded with gold nanoparticles (Au NPs) and chemotherapeutic drug toyocamycin (Au/Toy@G3 NGs) for ultrasound‐enhanced cancer theranostics is showcased. The constructed hybrid NGs with a size of 193 nm possess good colloidal stability under physiological conditions, and can be dissociated to release Au NPs and Toy in the reductive glutathione‐rich tumor microenvironment (TME). The released Toy can promote the apoptosis of cancer cells through endoplasmic reticulum stress amplification and cause immunogenic cell death to maturate dendritic cells. The loaded Au NPs can induce the conversion of tumor‐associated macrophages from M2‐type to antitumor M1‐type to remodulate the immunosuppressive TME. Combined with antibody‐mediated immune checkpoint blockade, effective chemoimmunotherapy of a pancreatic tumor mouse model can be realized, and the chemoimmunotherapy effect can be further ultrasound enhanced due to the sonoporation‐improved tumor permeability of NGs. The developed Au/Toy@G3 NGs also enable Au‐mediated computed tomography imaging of tumors. The constructed responsive dendrimeric NGs tackle tumors through a multi‐pronged chemoimmunotherapy strategy targeting both cancer cells and immune cells, which hold a promising potential for clinical translations.