Synergic cancer chemo-immunotherapy comprising combined doxorubicin and siRNA targeting CD47 co-delivered by a bola-amphiphilic dendrimer

Abstract

Restoring antitumor immunity while enhancing chemotherapy efficacy represents an optimistic strategy for cancer treatment. Enabling macrophage-mediated phagocytosis of cancer cells is pivotal for rehabilitating effective immune responses.However, its efficacy is often limited by elevated anti-phagocytic signals, such as CD47, and insufficient pro-phagocytic signals on cancer cells. We employed a synergic chemo-immunotherapeutic approach involving the chemotherapeutic agent doxorubicin (DOX) together with siRNA targeting CD47 (siCD47), co-delivered by a bola-amphiphilic dendrimer (bola4A) as nanocarrier. The co-delivery system (bola4A/DOX/siCD47) was established by encapsulating DOX within the hydrophobic interior of dendrimer nanomicelles, while complexing the negatively charged siCD47 to the positively charged dendrimer surface. The bola4A/DOX/siCD47 effectively downregulated CD47 expression and attenuated the CD47-signal regulatory protein α (SIRPα) axis-mediated anti-phagocytic signal. Concurrently, DOX induced immunogenic cell death (ICD), significantly increased the exposure of calreticulin (CALR), a pro-phagocytic signal that elicits immune response. Consequently, bola4A/DOX/siCD47 enhanced phagocytosis of tumor cells by macrophage and reprogrammed the tumor immunosuppressive microenvironment (TME) towards enhanced macrophage phagocytosis, dendritic cell maturation, T cell infiltration, and elevated secretion of pro-inflammatory cytokines. Altogether, bola4A/DOX/siCD47 exhibited a potent antitumor effect through the coordinated action of DOX with siCD47, and offers a promising approach for synergistic cancer chemo-immunotherapy.