Rizkallah Joe, Charbel Nicole, Yassine Abdallah, El Masri Amal, Raffoul Chris, El Sardouk Omar, Ghezzawi Malak, Abou Nasr Therese, Kreidieh Firas
Department of Diagnostic Radiology, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon.
Pharmaceutics. 2025 Aug 6;17(8):1019. doi: 10.3390/pharmaceutics17081019.
Melittin, a cytolytic peptide derived from honeybee venom, has demonstrated potent anticancer activity through mechanisms such as membrane disruption, apoptosis induction, and modulation of key signaling pathways. Melittin exerts its anticancer activity by interacting with key molecular targets, including downregulation of the PI3K/Akt and NF-κB signaling pathways, and by inducing mitochondrial apoptosis through reactive oxygen species generation and cytochrome c release. However, its clinical application is hindered by its systemic and hemolytic toxicity, rapid degradation in plasma, poor pharmacokinetics, and immunogenicity, necessitating the development of targeted delivery strategies to enable safe and effective treatment. Nanoparticle-based delivery systems have emerged as a promising strategy for overcoming these challenges, offering improved tumor targeting, reduced off-target effects, and enhanced stability. This review provides a comprehensive overview of the mechanisms through which melittin exerts its anticancer effects and evaluates the development of various melittin-loaded nanocarriers, including liposomes, polymeric nanoparticles, dendrimers, micelles, and inorganic systems. It also summarizes the preclinical evidence for melittin nanotherapy across a wide range of cancer types, highlighting both its cytotoxic and immunomodulatory effects. The potential of melittin nanoparticles to overcome multidrug resistance and synergize with chemotherapy, immunotherapy, photothermal therapy, and radiotherapy is discussed. Despite promising in vitro and in vivo findings, its clinical translation remains limited. Key barriers include toxicity, manufacturing scalability, regulatory approval, and the need for more extensive in vivo validation. A key future direction is the application of computational tools, such as physiologically based pharmacokinetic modeling and artificial-intelligence-based modeling, to streamline development and guide its clinical translation. Addressing these challenges through focused research and interdisciplinary collaboration will be essential to realizing the full therapeutic potential of melittin-based nanomedicines in oncology. Overall, this review synthesizes the findings from over 100 peer-reviewed studies published between 2008 and 2025, providing an up-to-date assessment of melittin-based nanomedicine strategies across diverse cancer types.
蜂毒肽是一种源自蜜蜂毒液的细胞溶解肽，已通过膜破坏、诱导凋亡以及调节关键信号通路等机制展现出强大的抗癌活性。蜂毒肽通过与关键分子靶点相互作用发挥其抗癌活性，包括下调PI3K/Akt和NF-κB信号通路，并通过产生活性氧和释放细胞色素c诱导线粒体凋亡。然而，其临床应用受到全身毒性、溶血毒性、在血浆中快速降解、药代动力学不佳以及免疫原性的阻碍，因此需要开发靶向递送策略以实现安全有效的治疗。基于纳米颗粒的递送系统已成为克服这些挑战的一种有前景的策略，具有改善的肿瘤靶向性、降低的脱靶效应和增强的稳定性。本综述全面概述了蜂毒肽发挥抗癌作用的机制，并评估了各种负载蜂毒肽的纳米载体的发展，包括脂质体、聚合物纳米颗粒、树枝状大分子、胶束和无机系统。它还总结了蜂毒肽纳米疗法在多种癌症类型中的临床前证据，突出了其细胞毒性和免疫调节作用。讨论了蜂毒肽纳米颗粒克服多药耐药性并与化疗、免疫疗法、光热疗法和放射疗法协同作用的潜力。尽管在体外和体内研究中取得了有前景的结果，但其临床转化仍然有限。关键障碍包括毒性、生产规模扩大、监管批准以及需要更广泛的体内验证。未来的一个关键方向是应用计算工具，如基于生理的药代动力学建模和基于人工智能的建模，以简化开发并指导其临床转化。通过集中研究和跨学科合作应对这些挑战对于实现基于蜂毒肽的纳米药物在肿瘤学中的全部治疗潜力至关重要。总体而言，本综述综合了2008年至2025年间发表的100多篇同行评审研究的结果，对基于蜂毒肽的纳米医学策略在不同癌症类型中的应用进行了最新评估。
