Lysosomal aggregation of iron nanoparticles guided by multistage transformation induces potent ferroptosis

Ferroptosis, a cell death form driven by lipid peroxidation accumulation via iron-dependent Fenton reaction, has attracted substantial attention in cancer therapy. This process is strictly dependent on iron ion concentration and environmental acidity. However, the relatively weak acidity in the tumor cytoplasm may significantly impair the Fenton catalytic activity of endocytosed iron-based nanoparticles. Inspired by the intrinsic acidic vesicular compartments of tumoral lysosomes, a multistage size-switching strategy is proposed to effectively target the optimal "battlefields" for iron-based materials. Through rational engineering, nanotransformers (NTF) integrated with collagenase (CLG) achieve targeted disassembly for deep tumor penetration and lysosomal aggregation to sustain Fenton catalytic activity. Enlarged iron depots in lysosomes prevent exocytosis, ensuring prolonged catalytic generation of lipid peroxidation species to initiate and amplify ferroptosis, ultimately inducing lysosomal membrane permeabilization and altered organelle functions. Further analysis reveals that iron nanoparticle lysosomal aggregation-mediated ferroptosis can effectively trigger immunogenic cell death and elicit robust antitumor immune responses. This work demonstrates the potential of well-designed multistage size-switchable nanotransformers in cancer treatment, representing a paradigm shift in advancing iron-based nanoparticle-mediated ferroptosis therapy.