Biomimetic O2 Self-generated hybrid membrane nanoplatform for blocking the polarization towards immunosuppressive M2 macrophage phenotype and enhancing sonodynamics therapy in orthotopic colorectal cancer

Abstract

Colorectal cancer is one of the most common intestinal tumors, of which occurrence and development are closely related to immune escape activity in vivo. Then, how to comprehensively block immune escape remains a big challenge for immunotherapy. Thus, a biomimetic nanoprobe Ce6@ZIF-8/hybrid membrane/PA (CZ@HP) is designed by coating Ce6 loaded ZIF-8 with a hybrid membrane composed of neutrophil membrane (Nm) & red blood cell membrane (Rm), accompanied by palmitoyl ascorbate (PA) to achieve reprogramming of immunosuppressive tumor microenvironment (TME) and enhancement of sonodynamics therapy (SDT) in hypoxic tumor. Cell and animal experiments indicate that, the CZ@HP probe can specifically target tumor at the inflammatory site, and it can effectively reduce the adsorption of neutrophils, then inhibit the polarization toward immunosuppressive M2 macrophage phenotype. Immunofluorescence staining and ELISA experiments demonstrate that PA and Rm can generate O2 and significantly improve the hypoxic environment, it enhances the polarization of anti-tumor M1 macrophages and regulate related cytokines, meanwhile improves the therapeutic effect of SDT. The survival rate of mice is elevated to 100% within 60 d. Overall, this O2 self-generated biomimetic hybrid membrane nanoprobe can block immune escape from various aspects and obtain enhanced SDT effect, then increase the treatment efficiency of inflammatory tumor, significantly improve the prognosis and elevate the survival rate of mice, providing a new idea for the clinical diagnosis and treatment of colitis-associated tumors.