Anti‐CD47 antibody‐decorated and cisplatin‐containing mesoporous silica nanoparticles for targeted chemoimmunotherapy of colorectal cancer in a patient‐derived organoids xenograft model

Abstract For colorectal cancer (CRC), treatment outcomes and prognosis remain poor even when using first‐line chemotherapeutics and immunotherapeutics. The main reasons include (i) lack of tumor specificity, severe off‐target cytotoxicity leading to adverse side effects, and occurrence of chemoresistance, and (ii) the immunosuppressive “cold” tumor microenvironment (TME). Herein, we demonstrate an example of highly efficient targeted CRC chemoimmunotherapy with cisplatin (CDDP)‐containing nanomedicine (CDDP@MSN‐Anti‐CD47) in a patient‐derived organoids xenograft model. The CDDP@MSN‐Anti‐CD47 is composed of CDDP‐loaded mesoporous silica nanoparticles with superficially functionalized anti‐CD47 antibodies to target cluster of differentiation CD47, a transmembrane integrin‐associated protein that is over‐expressed in CRC cells and can bind with signal regulatory protein α on tumor‐associated macrophages (TAMs) to maintain the immunosuppressive TME. Our results demonstrated that CDDP@MSN‐Anti‐CD47 achieved targeted delivery of CDDP to CRC cells with extended release, and induced reactive oxygen species overproduction to inhibit CRC cells and CRC patient‐derived organoids growth via activating caspase‐3‐related apoptosis and immunogenic cell death. DAMPs released following CDDP@MSN‐Anti‐CD47 treatment promoted the polarization of TAMs from immunosuppressive M2 to pro‐inflammatory M1 phenotype and also synergized with the functionalized anti‐CD47 antibodies to restore macrophage phagocytic activity against CRC cells. In both CRC cell and patient‐derived organoid xenograft models, CDDP@MSN‐Anti‐CD47 could specifically target the tumor, showing strong anti‐tumor effects, prolonged survival rate, and low systemic cytotoxicity. Overall, CDDP@MSN‐Anti augments combination chemotherapy and immunotherapy, and can be developed as a novel and promising strategy for the clinical treatment of CRC.