NIR-II Light-driven genetically edited nanoparticles with inherent CRT-inducing capability for macrophage-mediated immunotherapy

Abstract

Effectively activating macrophages to ‘eat’ tumor cells have great potential in cancer immunotherapy. However, tumor cells can express CD47 to evade macrophages, and secrete immunosuppressive factors to polarize macrophages into a pro-tumorigenic M2 phenotype. Herein, PEI-coated Au nanorods with an inherent capability to induce calreticulin (CRT) exposure were prepared and then used to electrostatically adsorb the CRISPR/Cas9 plasmid pH330/sgCD47, generating AuPpH330/sgCD47 nanocomplexes. The efficient induction of CRT exposure by AuPpH330/sgCD47 nanocomplexes provides additional “eat-me” signals to macrophages, especially under a 1064 nm laser. Meanwhile, AuPpH330/sgCD47 nanocomplexes under a 1064 nm laser activated the HSP70 promoter of pH330/sgCD47 to drive CD47 genomic disruption to suppress “don’t eat-me” signals. Therefore, AuPpH330/sgCD47 treatment synergistically promoted the macrophage phagocytosis of tumor cells and increased M2-to-M1 macrophage repolarization, which stimulates a potent immune response to inhibit tumor growth and lung metastasis. These HSP70 promoter-driven genetically edited nanoparticles represent a promising strategy for macrophage-mediated cancer immunotherapy.