Biomimetic Mineralized DCPA/ anti-CD47 containing Thermo-Sensitive Injectable Hydrogel for Bone-metastatic Prostate Cancer Treatment

Strategies that leverage the phagocytic capabilities of M1 macrophages against tumor cells are currently being investigated for cancer treatment. However, the clinical application of these strategies is significantly hampered by the severe side effects associated with conventional M1 macrophage activators. In this study, biomimetic mineralized dicalcium phosphate anhydrous (MDCPA) was synthesized using Zein as an organic template, aiming to promote M1 macrophage polarization effectively while minimizing side effects. In vitro experiments demonstrated that MDCPA can be engulfed by macrophages and induce M1 macrophage polarization. By combining the stimulation of MDCPA with a commonly used immune checkpoint inhibitor, anti-CD47 (aCD47), the macrophages exhibited the highest phagocytic activity toward prostate cancer cells. Further in vivo experiments illustrated significant tumor suppression and reduced bone resorption in a prostate cancer bone metastasis model utilizing MDCPA/aCD47-containing thermos-sensitive injectable hydrogels (MDCPA/aCD47 TSI gel). Mechanistic studies indicated that the MDCPA/aCD47 TSI gel promotes tumor cell apoptosis not only through the phagocytosis of tumor cells mediated by M1 macrophages, but also by activating anti-tumor CD8-positive T cells. Consequently, this composite gel platform presents an effective theragnostic strategy for treating prostate cancer bone metastasis without the associated side effects, facilitated by biomimetic minerals that mediate anti-tumor immunity.