Cooperative Self-Assembled Nanoparticle Induces Sequential Immunogenic Cell Death and Toll-Like Receptor Activation for Synergistic Chemo-immunotherapy.

Anticancer immunotherapy is hampered by poor immunogenicity and a profoundly immunosuppressive microenvironment in solid tumors and lymph nodes. Herein, sequential pH/redox-responsive nanoparticles (SRNs) are engineered to activate the immune microenvironment of tumor sites and lymph nodes. The two-modular SRNs could sequentially respond to the acidic tumor microenvironment and endosome compartments of dendritic cells (DCs) to precisely deliver doxorubicin (DOX) and imidazoquinolines (IMDQs). In the tumor microenvironment, released DOX triggers immunogenic cell death. In sentinel lymph nodes, the IMDQ nanoparticle module is dissociated in the acidic endosome compartment to specifically stimulate toll-like receptor 7/8 for DC maturation. Thus, the orchestrated nanoparticle system could enhance the infiltration of CD8α ⁺ T cells in tumors and provoke a strong antitumor immune response toward primary and abscopal tumors in B16-OVA and CT26 tumor-bearing mice models. The cooperative self-assembled nanoparticle strategy provides a potential candidate of nanomedicine to advance the synergistic cancer chemo-immunotherapy.