J Control Release. 2026 Nov 1:115510. doi: 10.1016/j.jconrel.2026.115510. Online ahead of print.
ABSTRACT
Ferroptosis induced by Fenton-reaction holds great promise in triple-negative breast cancer (TNBC) therapy. However, its efficacy is severely constrained by limited endogenous hydrogen peroxide (HO) substrates and poor Fenton reaction efficiency. To overcome these limitations, we propose a strategy to initiate a heterogeneous photo-Fenton-like reaction in HO-rich lysosomes and design a reaction engine for amplified cascade toxic oxidative radical propagation (REACTOR), which can confine the reaction to lysosomes for light triggering and accelerate it with p-benzoquinone (DMBQ). The REACTOR nanoplatform encapsulates copper-enriched Prussian blue (CuPB) and a redox-active DMBQ within thermosensitive liposomes, enabling preferential accumulation in lysosomes. Under irradiation, REACTOR triggers lipid phase transition, exposing the co-encapsulated CuPB and DMBQ to the lysosomal HO pool and initiating a highly efficient Fenton reaction that induces lysosomal membrane lipid peroxidation. Concurrently, ferrous ions released from lysosomal stores, together with CuPB-catalyzed quinone redox cycle, propagate oxidative damage to mitochondrial membranes, culminating in an explosive burst of lipid peroxides that efficiently triggers ferroptosis. REACTOR combined with irradiation significantly inhibits tumor growth, even achieving complete tumor regression and effectively suppressing metastasis in a TNBC-model. This light-activatable REACTOR transitions from a ready to a reactive state by mimicking the bombardier beetle's defense strategy, leveraging the lysosomal compartment to trigger, amplify, and sustain oxidative damage, offering a highly efficient and low-toxicity platform for precision cancer therapy.
PMID:42967530 | DOI:10.1016/j.jconrel.2026.115510