Nanoparticle-Mediated CD47-SIRPα Blockade and Calreticulin Exposure for Improved Cancer Chemo-Immunotherapy

Enabling macrophages to phagocytose tumor cells holds great potential for cancer therapy but suffers from tremendous challenges because the tumor cells upregulate antiphagocytosis molecules (such as CD47) on their surface. The blockade of CD47 alone is insufficient to stimulate tumor cell phagocytosis in solid tumors due to the lack of eat me signals. Herein, a degradable mesoporous silica nanoparticle (MSN) is reported to simultaneously deliver anti-CD47 antibodies (aCD47) and doxorubicin (DOX) for cancer chemo-immunotherapy. The codelivery nanocarrier aCD47-DMSN was constructed by accommodating DOX within the mesoporous cavity, while adsorbing aCD47 on the surface of MSN. aCD47 blocks the CD47-SIRP alpha axis to disable the don't eat me signal, while DOX induces immunogenic tumor cell death (ICD) for calreticulin exposure as an eat me signal. This design facilitated the phagocytosis of tumor cells by macrophages, which enhanced antigen cross-presentation and elicited efficient T cell-mediated immune response. In 4T1 and B16F10 murine tumor models, aCD47-DMSN generated a strong antitumor effect after intravenous injection by increasing tumor-infiltration of CD8+ T cells. Taken together, this study offers a nanoplatform to modulate the phagocytosis of macrophages for efficacious cancer chemo-immunotherapy.

Automated summary

A degradable mesoporous silica nanoparticle (MSN) has been developed for simultaneous delivery of anti-CD47 antibodies (aCD47) and doxorubicin (DOX) in cancer chemo-immunotherapy. The nanocarrier, aCD47-DMSN, blocks the CD47-SIRP alpha axis and induces immunogenic tumor cell death for enhanced phagocytosis by macrophages. This study provides a promising nanoplatform for modulating macrophage phagocytosis in cancer therapy.