Engineered macrophage nanoparticles enhance microwave ablation efficacy in osteosarcoma via targeting the CD47-SIRPα Axis: A novel Biomimetic immunotherapeutic approach

Osteosarcoma (OS) is a lethal bone tumor that primarily affects adolescents. OS is characterized by a high incidence of recurrence following surgical intervention, which is attributed to the presence of residual microscopic disease. Tumor-associated macrophages, which dominate the tumor microenvironment, often suppress immune responses and facilitate tumor progression and recurrence. This study developed an innovative nanotherapeutic approach by utilizing genetically engineered macrophage membranes with M1 polarization, stably overexpressing signal regulatory protein alpha (SIRPα), to encapsulate microwave-responsive nano-Prussian blue (SIRPα-M@nanoPB) nanoparticles. These nanoparticles induce tumor cell death selectively through hyperthermia and microwave dynamic effects upon targeted microwave irradiation. It is of critical importance to note that the enhancement of SIRPα on the nanoparticle surface actively targets and binds CD47 of tumor cells, thereby disrupting the "don't-eat-me" signal and effectively countering the immunosuppressive tumor environment. This action restores macrophage phagocytosis with M1 polarization, triggering potent immune responses. Our strategy holds considerable promise when it comes to improving the efficacy of microwave ablation through immune modulation, while reducing thermal damage to adjacent normal tissue and minimizing the risk of tumor recurrence. Thus, it offers a significant advancement in microwave therapies for patients with OS. • This study successfully developed a novel nanotherapeutic, SIRPα-M@nanoPB, by encapsulating engineered cell membranes onto microwave-responsive nanoPB. • The successful encapsulation and retention of the cell membrane were confirmed through western blotting, electron microscopy, and the presence of proteins on the membrane surface. • SIRPα-M@nanoPB demonstrated high cell compatibility and repeatable thermal effects, making it a promising candidate for clinical applications. • In vitro and in vivo experiments validated the significant regulatory role of macrophages in enhancing phagocytic and killing activity against tumor cells by disrupting the CD47-SIRPα immune-suppression checkpoint, and regulation of TAMs by SIRPα-M@nanoPB. • This innovative approach, synergistically combining thermotherapy and immunotherapy, holds considerable potential for safely treating residual OS tumors after surgery in clinical settings. • This innovative approach, synergistically combining thermotherapy and immunotherapy, holds considerable potential for safely treating residual OS tumors after surgery in clinical settings.