Bufalin-Loaded Multifunctional Nanodrugs for Cancer Therapy: Mechanisms, Delivery Strategies, and Translational...

Bufalin is a naturally occurring bufadienolide with broad-spectrum anticancer activity. Unlike conventional cytotoxic agents, bufalin exerts pleiotropic antitumour effects by directly modulating oncogenic proteins and promoting their degradation. It also disrupts metabolic plasticity, induces multiple forms of regulated cell death, counteracts therapeutic resistance, and remodels the immunosuppressive tumour microenvironment. However, the further application of bufalin is hindered by poor aqueous solubility, rapid systemic clearance, a narrow therapeutic window, and dose-limiting toxicity. Nanodrug delivery systems (NDDSs) offer a promising strategy for translating these interconnected pharmacological effects into spatially and temporally controlled therapeutic responses. This review summarises the distinctive anticancer mechanisms of bufalin and systematically evaluates the organic, inorganic, biomimetic, and hybrid nanocarriers developed for its delivery. Particular attention is given to tumour-responsive drug release, the targeting of cancer stem cells, the induction of ferroptosis and pyroptosis, metabolic modulation, sensitisation to phototherapy, and the activation of antitumour immunity. Finally, the major translational challenges are critically examined to inform the further rational development of bufalin-based nanomedicines.