Core-shell tecto dendrimers co-deliver drug/gene for immunomodulation of macrophages and dendritic cells and checkpoint blockade-promoted breast cancer chemoimmunotherapy

Development of an advanced drug formulation to cancer cells that can result in immunomodulation of multiple immune cells for enhanced cancer immunotherapy remains to be challenging. Herein, we developed a codelivery strategy based on pH-sensitive core-shell tecto dendrimers (CSTDs) to simultaneously deliver CD47 siRNA and anticancer drug doxorubicin (DOX) to cancer cells to lead to downregulation of "don't eat me" signals through silencing the CD47 genes for enhanced macrophage recognition, and upregulation of "eat me" signals through chemotherapy-mediated calreticulin exposure for promoted dendritic cell (DC) maturation and subsequent cytotoxic T cell activation, respectively. We show that the developed pH-responsive CSTDs are a robust vector that can compress siRNA and physically load DOX simultaneously with a high loading efficiency and a loading content, and can fast release the drug in an acidic tumor microenvironment. Importantly, with the combined anti-cytotoxic T-lymphocyte-associated protein 4 antibody-mediated immune checkpoint blockade, the CSTDs-mediated drug/gene delivery enables synergistically promoted M1 polarization of macrophages and T cell-mediated immune responses to effectively inhibit both primary and distal murine breast tumors. Such a development of CSTD-based drug/gene co-delivery to cancer cells that can simultaneously modulate multiple immune cells provides new insights for enhanced immunotherapy of different types of cancer.