免疫佐剂作为肿瘤疫苗不可或缺的组成部分，可以显着增强抗肿瘤免疫的幅度、广度和持久性。然而，目前的免疫佐剂存在免疫原性弱、细胞内化不足、循环时间差、生物活性单一等问题。方法：在此，我们构建了 Fe3-紫草素金属酚网络 (FeShik) 纳米药物作为免疫原性细胞死亡 (ICD) 兴奋剂和用于肿瘤疫苗接种的多功能免疫佐剂。通过负载卵清蛋白（OVA）作为模型抗原构建OVA@FeShik纳米疫苗或负载4T1肿瘤细胞片段（TF）作为同源抗原构建TF@FeShik纳米疫苗，研究FeShik纳米药物的多功能性。体外检测包括GSH反应性、•OH生成、胶体稳定性、细胞摄取、铁死亡和坏死性凋亡的细胞毒性机制、ICD效应、促进DC成熟和抗原交叉呈递等。进行了体内药代动力学和生物分布、抗肿瘤作用、远隔作用、免疫记忆作用和生物安全性等观察。结果：FeShik纳米药物的存在可以显着延长抗原的血液循环时间，增加抗原的生物利用度。 FeShik纳米药物被肿瘤细胞吞噬后，可以响应肿瘤微环境分解成Fe2和紫草素，通过铁死亡和坏死性凋亡导致肿瘤细胞ICD。因此，ICD释放的自体肿瘤细胞裂解物和促炎细胞因子不仅刺激DC成熟和抗原交叉呈递，而且促进巨噬细胞复极化和细胞毒性T淋巴细胞浸润，从而激活针对实体瘤的适应性免疫反应。结论：总之，我们的FeShik超分子纳米药物整合了ICD兴奋剂和免疫佐剂的生物活性，例如根除肿瘤细胞、激活抗肿瘤免疫反应、调节免疫抑制肿瘤微环境以及免疫治疗后的生物降解。受多酚和金属离子多样性的鼓励，我们的研究可能为建立肿瘤疫苗接种大型库提供有价值的范例。©作者。

Immunoadjuvants, as an indispensable component of tumor vaccines, can observably enhance the magnitude, breadth, and durability of antitumor immunity. However, current immunoadjuvants suffer from different issues such as weak immunogenicity, inadequate cellular internalization, poor circulation time, and mono-functional bioactivity. Methods: Herein, we construct Fe3+-Shikonin metal-phenolic networks (FeShik) nanomedicines as immunogenic cell death (ICD) stimulants and multifunctional immunoadjuvants for tumor vaccination. The multifunctionality of FeShik nanomedicines is investigated by loading ovalbumin (OVA) as the model antigen to construct OVA@FeShik nanovaccines or 4T1 tumor cell fragment (TF) as homologous antigen to construct TF@FeShik nanovaccines. In vitro examinations including GSH responsive, •OH generation, colloid stability, cellular uptake, cytotoxicity mechanism of ferroptosis and necroptosis, ICD effect, the promotion of DC maturation and antigen cross-presentation were studied. In vivo observations including pharmacokinetics and biodistribution, antitumor effect, abscopal effect, immune memory effect, and biosafety were performed. Results: The presence of FeShik nanomedicines can significantly prolong the blood circulation time of antigens, increasing the bioavailability of antigens. Upon phagocytosis by tumor cells, FeShik nanomedicines can disassemble into Fe2+ and Shikonin in response to tumor microenvironments, leading to ICD of tumor cells via ferroptosis and necroptosis. Consequently, ICD-released autologous tumor cell lysates and pro-inflammatory cytokines not only stimulate DC maturation and antigen cross-presentation, but also promote macrophage repolarization and cytotoxic T lymphocyte infiltration, resulting in the activation of adaptive immune responses toward solid tumors. Conclusion: In a word, our FeShik supramolecular nanomedicines integrate bioactivities of ICD stimulants and immunoadjuvants, such as eradicating tumor cells, activating antitumor immune responses, modulating immunosuppressive tumor microenvironments, and biodegradation after immunotherapy. Encouraged by the diversity of polyphenols and metal ions, our research may provide a valuable paradigm to establish a large library for tumor vaccination.© The author(s).