Gossypol in the nanomedicine era: Overcoming clinical bottlenecks and unlocking antitumor potential

Gossypol, a natural polyphenolic compound derived from cotton plants, has garnered renewed interest as a potent multi-target agent for cancer therapy. This review offers a comprehensive and integrative evaluation of gossypol’s antitumor potential, encompassing its molecular mechanisms, pharmacological spectrum, clinical investigations, and nanotechnology-assisted delivery strategies. Mechanistically, gossypol functions as a BH3 mimetic that antagonizes Bcl-2 family proteins to induce mitochondrial apoptosis, while also modulating autophagy, cell cycle progression, oxidative phosphorylation, and DNA repair—enabling simultaneous disruption of multiple oncogenic pathways. Despite its promising preclinical efficacy, clinical translation has been hampered by dose-limiting toxicity, poor aqueous solubility, low bioavailability, and rapid systemic clearance. To overcome these challenges, this review highlights recent advances in nanomedicine that seek to optimize gossypol’s pharmacokinetics and therapeutic index. Liposomal, polymeric, and inorganic nanodelivery system have demonstrated enhanced solubility, tumor targeting, circulation time, and safety profiles. Notably, multifunctional nano-delivery platforms enable the co-delivery of gossypol with chemotherapeutics, photosensitizers, or immunomodulators, yielding synergistic effects and reduced adverse reactions. Stimuli-responsive nanostructures further facilitate controlled release in tumor microenvironments, enhancing therapeutic precision. By bridging the gap between gossypol’s complex pharmacology and the translational potential of smart nanodelivery system, this review outlines a strategic roadmap for repurposing gossypol as a viable candidate in next-generation cancer therapy.

棉酚是一种从棉花植物中提取的天然多酚化合物，作为一种有效的多靶点癌症治疗剂，重新引起了人们的兴趣。这篇综述对棉酚的抗肿瘤潜力进行了全面综合的评估，包括其分子机制、药理学谱、临床研究和纳米技术辅助的递送策略。从机制上讲，棉酚充当 BH3 模拟物，拮抗 Bcl-2 家族蛋白以诱导线粒体凋亡，同时还调节自噬、细胞周期进程、氧化磷酸化和 DNA 修复，从而能够同时破坏多种致癌途径。尽管其临床前疗效颇具前景，但其临床转化却因剂量限制性毒性、水溶性差、生物利用度低和快速全身清除而受到阻碍。为了克服这些挑战，本综述重点介绍了纳米医学的最新进展，旨在优化棉酚的药代动力学和治疗指数。脂质体、聚合物和无机纳米递送系统已被证明具有增强的溶解度、肿瘤靶向性、循环时间和安全性。值得注意的是，多功能纳米递送平台能够将棉酚与化疗药物、光敏剂或免疫调节剂共同递送，产生协同效应并减少不良反应。刺激响应纳米结构进一步促进肿瘤微环境中的受控释放，提高治疗精度。通过弥合棉酚复杂的药理学与智能纳米递送系统的转化潜力之间的差距，本综述概述了重新利用棉酚作为下一代癌症治疗的可行候选者的战略路线图。