Harnessing nanoparticles to unlock the therapeutic potential of triptolide in cancer treatment.

Cancer is the second leading cause of death globally, responsible for nearly 9.8 million deaths and 19.2 million new cases annually, a figure projected to rise to 13 million deaths and over 21 million new cases by 2030. Despite advances in diagnosis and therapy, limitations such as systemic toxicity, drug resistance, and non-specific targeting hinder effective treatment outcomes. Triptolide (TPL), a diterpenoid triepoxide derived from Tripterygium wilfordii Hook F, exhibits potent anticancer activity by inducing apoptosis, inhibiting angiogenesis, modulating immune responses, and sensitizing resistant cancer cells. However, its clinical utility is restricted by poor solubility, rapid metabolism, and multi-organ toxicity. Recent advancements in nanotechnology have enabled the development of nanocarrier-based delivery systems that improve TPL's bioavailability, pharmacokinetics, and tumor-targeting efficiency. Nanoplatforms such as polymeric nanoparticles, liposomes, micelles, dendrimers, and biomimetic vesicles allow controlled release, enhanced tumor accumulation, and reduced systemic toxicity. These systems also facilitate synergistic co-delivery with chemotherapeutics, overcoming multidrug resistance. This review comprehensively highlights the formulation strategies, mechanistic insights, and preclinical applications of TPL-loaded nanocarriers across various cancers, along with current challenges and translational perspectives. Collectively, nanocarrier-mediated TPL delivery offers a safer and more effective approach, redefining future directions in cancer therapy.