Engineered Nano-Micro Pyroptosis Generators: A Magnetic-Metallo-Immunotherapeutic Strategy to Reinforce Transarterial Embolization

Gasdermin-mediated pyroptosis represents a promising immunotherapeutic strategy, yet requires precise tumor-specific activation. Magnetic hyperthermia therapy (MHT) has the potential to induce pyroptosis in hepatocellular carcinoma (HCC), while its efficacy is limited by suboptimal heating efficiency and tumor resistance. Herein, we developed an innovative magnetic-metallo-immunotherapeutic platform by engineering nanomicro pyroptosis generators, thereby enhancing transarterial embolization (TAE). Through compositional and structural optimization, Zn-Fe₃O₄@Co-Fe₃O₄ core-shell nanocubes (ZnCo-Fe₃O₄ CSNCs) with enhanced magnetothermal properties were obtained, which exhibited significantly improved saturation magnetization (Ms) and coercivity (Hc). These nanocubes were further assembled via microfluidic technology into magnetic microspheres (MSs) with tunable sizes, integrating the therapeutic functions of TAE and MHT. Under an alternating magnetic field (AMF), the ZnCo-Fe₃O₄ MSs demonstrated temperature-dependent ion release and localized hyperthermia while simultaneously inhibiting heat shock protein (HSP) upregulation through metabolic interference. This orchestrated therapeutic cascade effectively triggered pyroptosis in cancer cells, subsequently activating the immune response and thereby enhancing the efficacy of magnetic-metallo-immunotherapy. The strategic combination of this platform with immune checkpoint blockade (ICB) therapy provoked comprehensive systemic immune activation, markedly enhancing treatment efficacy and suppressing the progression of both primary tumors and distant tumors. Notably, ZnCo-Fe₃O₄ MSs demonstrated an exceptional capacity to modulate the immunosuppressive tumor niche while substantially improving TAE performance through their unique embolization-immunomodulation functionality. Overall, this study highlights new avenues for exploring pyroptosis-mediated magnetic-metallo-immunotherapy for effective cancer therapy.