Triple‐Action Semiconducting Ferrocene‐Prodrug Nanotherapeutics for Sequentially Sonodynamic‐Adjuvant Ferroptosis‐Immunotherapy of Deep Tumors

Ferroptosis-immunotherapy can be used for treating cancer with improved effect relative to sole therapeutic strategy. While this combination therapy primarily relies on systemic administration of ferroptosis inducers and immunomodulators, which will result in poor tumor selectivity, suboptimal therapeutic bioavailability, and potential off-target toxicities. This study reports semiconducting polymer (SP) ferrocene-prodrug nanotherapeutics (SPN_Fc@αP) that enable precise control over both ferroptosis and immunotherapy with sonodynamic-adjuvant for deep tumor therapy. SPN_Fc@αP integrate a semiconducting polymer as sonosensitizer and a ferrocene prodrug, with the surface embellishing of antibody against programmed death-ligand 1 (PD-L1) via reactive oxygen species (ROS)-cleavable linker. This nanotherapeutic system generates ROS via sonodynamic effect under ultrasound irradiation, which leads to ferrocene-prodrug activation for ferroptosis and sequential αPD-L1 release for inducing antitumor immune response. In both tissue-covered subcutaneous tumors and orthotopic pancreatic cancer models, SPN_Fc@αP-based treatment leads to complete tumor regression, effective metastasis inhibition and 100% mouse survival rates. This sonodynamic-ferroptosis-immunotherapy triple-action approach reprograms the tumor microenvironment by promoting CD8⁺ T cell infiltration and suppressing regulatory T cells, contributing to a considerable antitumor efficacy. Via integrating precisely controlled activation, ferroptosis induction and immune modulation, such nanotherapeutics offer a powerful platform for treating aggressive and therapy-resistant tumors.