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

• Gossypol is a multi-target natural BH3 mimetic that simultaneously regulates apoptosis, autophagy, metabolism, DNA repair, and inflammatory signaling across diverse tumor types. • Despite extensive preclinical activity, the clinical translation of gossypol is severely limited by dose-limiting toxicity, poor solubility, rapid clearance, and a narrow therapeutic window. • Nanotechnology-based delivery systems markedly improve gossypol pharmacokinetics, tumor accumulation, and safety profiles, enabling controlled release and spatiotemporal precision. • Multifunctional nanoplatforms facilitate synergistic combination therapies by co-delivering gossypol with chemotherapeutics, photosensitizers, or immunomodulators. • This review integrates mechanistic insights, clinical outcomes, and nanoengineering strategies to provide a roadmap for repurposing gossypol in next-generation cancer therapy. 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. This review systematically elucidates gossypol’s multi-target anticancer mechanisms and highlights nanotechnology-enabled delivery strategies that overcome its pharmacokinetic limitations, paving the way for its clinical translation in next-generation cancer therapy.