Tme-responsive porphyrin-based Mn-MOF/Erastin nanotherapeutic synergistically triggers cascading ferroptosis for hepatocellular carcinoma therapy

• Design of a dual-stimuli-responsive nanocarrier that degrades in response to acidic pH and H 2 O 2 in the TME, enabling precise spatiotemporal release of Erastin and Mn 2+ . • Propels a cascading amplification of ferroptosis by combining Erastin-induced system Xc − inhibition and Mn 2+ -dependent GSH depletion/·OH generation. • Superior in vivo performance with enhanced tumor accumulation, significant tumor regression, and excellent biocompatibility, supporting its potential for clinical translation. Hepatocellular carcinoma (HCC) persists as a global health burden, with treatment challenges arising from the drug resistance and systemic toxicity of current therapeutic approaches. Ferroptosis, an iron-dependent form of regulated cell death, represents a promising strategy for cancer therapy. However, ferroptosis inducers such as Erastin face limitations due to poor bioavailability and lack of tumor specificity. Capitalizing on the distinctive tumor microenvironment (TME) of HCC, this study engineered a TME-responsive nanoplatform (Mn-MOF/Erastin) utilizing a manganese porphyrin-based metal–organic framework (Mn-MOF) as the core carrier. This framework encapsulates the ferroptosis inducer Erastin to synergistically trigger cascading ferroptosis amplification for HCC therapy. The Mn-MOF/Erastin nanotherapeutic demonstrates well-defined morphology, high drug loading, TME-triggered degradation, and potent reactive oxygen species (ROS) generation. In vitro, Mn-MOF/Erastin depletes intracellular glutathione (GSH) indirectly via Mn 2+ and catalyzes toxic hydroxyl radical (•OH) production through Fenton-like reactions and peroxidase-like activity. •OH directly propagates lipid peroxidation. Concurrently, Erastin inhibits system Xc − , blocking the uptake of cystine and thereby preventing the synthesis of new GSH. This synergistic dual assault, Mn-MOF consuming existing GSH while Erastin cutting off the GSH supply, leads to a catastrophic collapse of the cellular antioxidant defense. The resulting failure to neutralize lipid peroxides through the GPX4 pathway culminates in potent ferroptosis. In vivo, Mn-MOF/Erastin effectively targets HCC tumors, enabling localized drug accumulation. This nanoplatform significantly inhibits tumor growth in orthotopic models while minimizing systemic toxicity, concurrently upregulating key ferroptosis markers. Collectively, this “three-in-one” nanotherapeutic exploits TME characteristics to initiate cascading ferroptosis amplification, presenting a potent and precise strategy for HCC treatment.