Macrophage Drug Delivery System Overexpressing Non-secretory TNF-α for Targeted Therapy of Colorectal Cancer

OBJECTIVE To construct an intelligent cell carrier system that has controllable near-infrared light response capability and can be thermally blasted "on demand" to achieve localized release of tumor necrosis factor α(TNF-α) protein in tumor tissues for targeted therapy of colorectal cancer. METHODS This project modified macrophages to overexpress non-secretory TNF-α effector protein(M^ET) through genetic engineering technology and prepared sericin nanoparticles (ICG@SNP) equipped with the photosensitizer indocyanine green(ICG) as a switch for the release of intracellular drug protein through materials science methods. Utilizing the strong phagocytic properties of macrophages, M^ET was loaded with the ICG@SNP with fluorescence characteristics and photothermal conversion effect. To evaluate the biological activity and existence form of TNF-α protein overexpressed in macrophages, the uptake and retention efficiency of ICG@SNP nanoparticles by M^ET cells, and the ability of ICG@SNP@M^ET to release TNF-α protein triggered by near-infrared light(NIR) in vitro. To evaluate the tumor-homing ability and anti-tumor effect of the functionalized macrophages in vivo. RESULTS The TNF-α protein in M^ET cells had biological activity and was stably present in macrophages in a non-secreted form, the uptake and retention efficiency of ICG by macrophages had been enhanced through sericin nanoparticles, and ICG@SNP@M^ET could be thermally "blasted" to release biologically active TNF-α effector protein triggered by NIR. This study also preliminarily verified that ICG@SNP@M^ET could migrate and penetrate into the tumor site in the CT26 tumor-bearing mouse model of subcutaneous colon cancer, and exhibited excellent anti-tumor activity combined with NIR irradiation. CONCLUSION The ICG@SNP@M^ET drug delivery system can be targeted to the colorectal cancer and release TNF-α effector protein triggered by NIR to play an anti-tumor therapeutic effect.