作为一种天然的溶血肽，蜂毒素（Mel）具有强烈的细胞溶解活性，并是一种强效的癌症治疗肽。然而，Mel的严重溶血活性在很大程度上阻碍了其临床应用。在本研究中，基于蛋白质/肽和多酚之间的强相互作用，我们开发了一种以丹宁酸-Fe3+ 金属-酚网络（MPN）为基础的策略，可以通过屏蔽其正电荷和减少其溶血活性，将Mel从敌人转化为朋友。此外，我们还引入了一种免疫佐剂resiquimod（R848）用于免疫刺激，提供最终的Mel和R848共载纳米药物。Mel引起的膜破坏可以诱导免疫细胞死亡用于免疫刺激，R848可以作为免疫佐剂进一步促进免疫刺激效应，而丹宁酸-Fe3+ MPN介导的费托反应可以产生反应性氧化物用于癌症治疗。进一步的实验表明，纳米药物能够有效地诱导肿瘤细胞的免疫细胞死亡，并引起强烈的肿瘤内和系统性抗肿瘤免疫刺激。在双侧肿瘤携带的小鼠模型中，纳米药物能够显著破坏原发性肿瘤，并提高远处肿瘤的造影效果。总之，MPN促进的“敌人变朋友”策略可以促进Mel的实际应用，并促进癌症免疫治疗的发展。Copyright © 2023 Yuxin Guo等人。

As a naturally occurring cytolytic peptide, melittin (Mel) has strong cytolytic activity and is a potent therapeutic peptide for cancer therapy. However, the serious hemolytic activity of Mel largely impedes its clinical applications. In this work, based on the strong interactions between proteins/peptides and polyphenols, we develop a tannic acid-Fe3+ metal-phenolic network (MPN)-based strategy that can convert Mel from foe to friend via shielding its positive charges and reducing its hemolytic activity. Besides, an immune adjuvant resiquimod (R848) is also introduced for immunostimulation, affording the final Mel- and R848-coloaded nanodrug. The Mel-caused membrane disruption can induce immunogenic cell death for immunostimulation, R848 can act as an immune adjuvant to further facilitate the immunostimulatory effect, and the tannic acid-Fe3+ MPN-mediated Fenton reaction can produce reactive oxygen species for cancer treatment. Further experiments reveal that the nanodrug can effectively cause immunogenic cell death of tumor cells and arouse robust intratumoral and systemic antitumor immunostimulation. In the bilateral tumor-bearing mouse models, the nanodrug considerably destroys the primary tumor and also boosts the abscopal effect to ablate the distant tumor. Collectively, the MPN-facilitated "foe-to-friend" strategy may promote the practical applications of Mel and foster the development of cancer immunotherapeutics.Copyright © 2023 Yuxin Guo et al.