Targeted microwave sensitizers reprogram cancer-associated fibroblasts via nitric oxide delivery to potentiate hepatocellular carcinoma therapy.

Microwave ablation (MWA) has emerged as a locoregional therapeutic modality for the management of various solid tumors. However, MWA often struggles to completely eliminate tumor cells without damaging surrounding healthy tissue. This triggers the persistence of an immunosuppressive microenvironment in the vicinity of residual tumors, leading to thermo-mediated tumor recurrence and metastasis. In the present study, we developed a multifunctional microwave ablation sensitizer (SNAP/MOF@HCM) by coating a biomimetic cancer cell-cancer-associated fibroblast membrane (HCM) onto a ZIF-8 (metal-organic framework, MOF) nanoparticle platform and co-encapsulating the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP). On the one hand, high-surface-area MOF can enrich cavity-internal ions, enhancing local thermal efficiency; On the other hand, the hybrid membrane confers dual targeting capabilities to the nanoparticles, allowing for their specific accumulation and efficient internalization within liver cancer tissues. During this process, the nanoparticles significantly enhanced heat and mass transfer by inhibiting the activation of cancer-associated fibroblasts (CAFs) and degrading the dense extracellular matrix, and opened up a green channel for immune cell infiltration, thereby reversing the CAFs-mediated immunosuppression. In addition, the zinc ions released by metal-organic frameworks can trigger Fenton-like reactions, generating hydroxyl radical, which, in synergy with the nitric oxide released by SNAP, amplify oxidative damage, induce tumor cell apoptosis and immunogenic cell death (ICD), and activate systemic anti-tumor immunity, thereby facilitating the complete eradication of tumor cells.