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Theranostics 2023; 13(15):5266-5289. doi:10.7150/thno.81650 This issue Cite

Research Paper

Fe(III)-Shikonin supramolecular nanomedicines as immunogenic cell death stimulants and multifunctional immunoadjuvants for tumor vaccination

Wenjie Feng¹, Wanrui Shi², Yanqi Cui², Jiajun Xu², Shuwei Liu¹, Hang Gao², Shoujun Zhu^1,2, Yi Liu^2,✉, Hao Zhang^1,2,3,✉

1. Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun 130021, P. R. China.
2. State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China.
3. Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou 450001, P. R. China.

✉ Corresponding author: E-mail addresses: yiliuchemedu.cn; hao_zhangedu.cn.

Abstract

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.

Keywords: shikonin, metal-phenolic networks, nanomedicines, immunogenic cell death, immunoadjuvants, tumor nanovaccines

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