Promoción de la ferroptosis mediada por hierro endógeno para la terapia del cáncer mediante interferencia génica y...

Ferroptosis, an iron-dependent form of regulated cell death, has emerged as an attractive strategy in cancer therapy. However, current approaches that deliver exogenous iron to induce ferroptosis suffer from off-target toxicity and are often thwarted by tumor cell iron-efflux defenses, necessitating an alternative strategy for promoted ferroptosis. Here, we report a spatially controlled nanoplatform that mobilizes the intracellular labile iron pool while concurrently dismantling antioxidant barriers, thereby amplifying endogenous iron-mediated ferroptotic damage. A glutathione (GSH)-responsive, disulfide-bridged metal-organic framework (MOF) co-encapsulating carbonic anhydrase IX (CA9)-targeted siRNA (siCA9) and the photosensitizer chlorin e6 (Ce6) was constructed (MOF-siCA9-Ce6). Once internalized by GSH-rich tumor cells, the framework collapses, liberating its payloads and consuming GSH to intensify oxidative stress. siCA9 knockdown acidifies the cytosol, mobilizing endogenous Fe²⁺, whereas laser-activated Ce6 generates detrimental reactive oxygen species (ROS) that further erode lipid repair systems. The resultant Fe²⁺/ROS surge drives lipid peroxidation and concurrent suppression of glutathione peroxidase 4 and ferroptosis-suppressor-protein 1, culminating in potent ferroptosis. Taken together, GSH/laser-activated MOF-siCA9-Ce6 elicits pronounced tumor inhibition both in vitro and in vivo. This endogenous‑iron-driven, ROS-amplified strategy establishes a versatile paradigm for well-tolerated and effective ferroptosis-based cancer therapy.