Extracellular Vesicles‐Derived Hybrid Nanoplatforms for Amplified CD47 Blockade‐Based Cancer Immunotherapy

Abstract

Immunomodulation of tumor‐associated macrophages (TAMs) into tumor‐inhibiting M1‐like phenotype is a promising but challenging strategy. Cleverly, tumor cells overexpress CD47, a “don't eat me” signal that ligates with the signal regulatory protein alpha (SIRPα) on macrophages to escape phagocytosis. Thus, effective re‐education of TAMs into the “eat me” type and blocking the CD47‐SIRPα signaling play pivotal roles in tumor immunotherapy. Herein, it is reported that hybrid nanovesicles (hEL‐RS17) derived from extracellular vesicles of M1 macrophages and decorated with RS17 peptide, an antitumor peptide that specifically binds to CD47 on tumor cells and blocks CD47‐SIRPα signaling, can actively target tumor cells and remodel TAM phenotypes. Consequently, more M1‐like TAMs infiltrate into tumor tissue to phagocytize more tumor cells due to CD47 blockade. By further co‐encapsulating chemotherapeutic agent shikonin, photosensitizer IR820, and immunomodulator polymetformin in hEL‐RS17, an enhanced antitumor effect is obtained due to the combinational treatment modality and close synergy among each component. Upon laser irradiation, the designed SPI@hEL‐RS17 nanoparticles exert potent antitumor efficacy against both 4T1 breast tumor and B16F10 melanoma models, which not only suppresses primary tumor growth but also inhibits lung metastasis and prevents tumor recurrence, exhibiting great potential in boosting CD47 blockade‐based antitumor immunotherapy.

Cells in the liver microenvironment regulate the process of liver metastasis

“…55 growth and metastasis, which is a marker of poor prognosis of tumor. 105 In the early stage of tumorigenesis, cancer cells produce chemokines (such as CXCL12) to recruit monocytes into the tumor microenvironment and finally mediate the transformation of monocytes into TAMs. 106 TAMs are macrophages that infiltrate tumor tissue or accumulate in the microenvironment of solid tumors.…”

“…Macrophages are mainly derived from blood monocytes produced by myeloid progenitor cells of bone marrow. It includes two types, the M1 type involved in tumor killing, and the M2 type involved in tumor growth and metastasis, which is a marker of poor prognosis of tumor 105 . In the early stage of tumorigenesis, cancer cells produce chemokines (such as CXCL12) to recruit monocytes into the tumor microenvironment and finally mediate the transformation of monocytes into TAMs 106 …”

Genetically engineered cell-derived nanovesicles for cancer immunotherapy

“…Thus, TAM-derived EVs are appealing candidates for immunomodulation and cancer immunotherapy. 43,44 M1 macrophages are the classically activated phenotypes that exert tumor-inhibiting abilities, while M2 macrophages are the alternatively activated counterparts that promote tumor progression and immunosuppression. In analogous to their parental cells, EVs derived from M1 macrophages have demonstrated that they not only possess tumor-homing ability, 45 but also can repolarize M2 macrophages to the M1 phenotype.…”

Chemoimmunotherapeutic Nanogel for Pre- and Postsurgical Treatment of Malignant Melanoma by Reprogramming Tumor-Associated Macrophages

“…Recently, growing evidence has demonstrated the potential of metformin in remodeling the tumor immune microenvironment from immunosuppressive condition to immunoactivated state. Specifically, metformin boosts the innate immune system by repolarizing TAM from M2-like to M1-like phenotypes, increasing the quantity and quality of CD8 + T cells, promoting the function and infiltration of natural killer (NK) cells, and suppressing tumor-promoting immune cells. − In our previous studies, we synthesized polymetformin (PolyMet) via the addition reaction between chitosan and dicyandiamide for synergistic tumor therapy. , In this present work, carboxymethyl chitosan (CMCS) was used to replace chitosan for the synthesis of PolyMet CMCS , which introduced free carboxyl groups in PolyMet. Then, PolyMet CMCS was chemically cross-linked with cystamine that contains free amino groups in its structure to form a nanogel network by the generated amide bond .…”

“…14−19 via the addition reaction between chitosan and dicyandiamide for synergistic tumor therapy. 20,21 In this present work, carboxymethyl chitosan (CMCS) was used to replace chitosan for the synthesis of PolyMet CMCS , which introduced free carboxyl groups in PolyMet. Then, PolyMet CMCS was chemically cross-linked with cystamine that contains free amino groups in its structure to form a nanogel network by the generated amide bond.…”