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

Abstract

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-SIRPα 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.

Improving nanochemoimmunotherapy efficacy by boosting “eat-me” signaling and downregulating “don't-eat-me” signaling with Ganoderma lucidum polysaccharide-based drug delivery

“…Previous studies have highlighted the significant tumor-suppressive effects of targeting CD47 using various approaches, such as antibodies, siRNA, and anti-sense morpholino. 73–76 As reported by Mohanty et al , CD47 antibodies monotherapy resulted in an impressive inhibition rate exceeding 50% against osteosarcomas. 73 Other CD47 regulators, including siRNA, morpholino and gefitinib, exhibited relatively modest efficacy on their own.…”

Multifunctional Tumor-Targeting Carbon Dots for Tumor Microenvironment Activated Ferroptosis and Immunotherapy in Cancer Treatment

“…Ferroptosis has been reported to induce ICD, which in turn activates systemic immune responses. ,, ICD of tumor cells is characterized by the release of damage-associated molecular patterns (DAMPs), which can act as an immunogenic signal to activate antitumor immune responses, such as surface-exposed calreticulin protein (CRT). , In this study, CT26 cells were treated with FG-CDs@Cu (0, 100, 200, and 300 μg mL –1 ), and anti-CRT-AF488 was used as an immunofluorescence probe to study the expression of CRT in cells. Figure f shows that no significant green fluorescence was found in untreated CT26 cells, indicating that there was no CRT extroversion to the outside of the cell membrane.…”

Enhancing Cancer Chemo‐Immunotherapy: Innovative Approaches for Overcoming Immunosuppression by Functional Nanomaterials

“…increasing ICD and reversing the tumor immunosuppressive microenvironment. [150,151] However, the approval of mesoporous silica nanoparticles by the FDA has been suspended due to their unknown biodistribution, limited biodegradation, and obscure clearance. [152] It is imperative to make effects on the investigation of clearance mechanisms to advance their clinical trials in the future.…”