Jundong Lin, Huikang Yang, Zhihao Zou, Lizhi Deng, Xiaoxia Cai, Muqi Chen, Jiayi Xu, Wenjun Yin, Biyan Wen, Wenjie Xie, QianFeng Xu, Guowei Zhong, Zhen Wu, Yanfei Chen, Rihong Zhang, Weicheng Tian, Yixun Zhang, Yusen Long, Yanfang Li, Zhaodong Han, Yuxiang Liang, Jianheng Ye, J‐H Lu, Yingke Liang, Qishan Dai, Fen Zou, Huichan He, Weide Zhong, Yangjia Zhuo
Docetaxel (Doc), a widely used chemotherapeutic agent, was limited by suboptimal therapeutic efficacy and dose-limiting systemic toxicity due to the insufficiency of hydrophilicity and tumor-targeting specificity. To address this limitation, we developed an amphiphilic ferrocene-based polymer, PPEGMA-b-PFMMA (PF), to co-encapsulate Doc and the photosensitizer IR808, forming photothermally responsive nanoparticles (NPs) termed P8D NPs. P8D NPs significantly improved the aqueous stability and tumor-specific accumulation of both agents by leveraging a hydrogen peroxide (H₂O₂)-triggered drug release mechanism within the tumor microenvironment. Under near‑infrared (NIR) irradiation, P8D NPs generated substantial heat and a burst of reactive oxygen species (ROS), promoting NPs disintegration and drug release. Mechanistically, Doc induced nuclear to cytoplasmic translocation of HMGB1, while photothermal/photodynamic therapy (PTT/PDT) facilitated the extracellular release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens via ferroptosis and cell membrane rupture. Together, these actions enhanced dendritic cells (DCs) maturation, antigen presentation and cytotoxic CD8⁺ T cell infiltration in tumor, thereby effectively reversing the immunosuppressive tumor microenvironment. Remarkably, this combination strategy not only inhibited the growth of distant tumors but also established long-term anti-tumor immunological memory to prevent recurrence. This study demonstrates that ferrocene-based nanocarrier-mediated PTT/PDT synergizes with Doc to reactivate antitumor immunity through ferroptosis-induced immunogenic cell death (ICD).