Iron‐siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation

Abstract

Ferrous iron (Fe 2 + ) has more potent hydroxyl radical ( * OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe 2 + can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe 0 nanoparticles (Fe 0 -siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe 0 -siRNA NPs are degraded to release Fe 2 + and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O 2 ). The accompanied O 2 depletion causes an intracellular pH decrease, which further promotes the degradation of Fe 0 -siRNA NPs. In addition to initiating chemodynamic process, Fe 2 + -catalyzed * OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulationenhanced CDT.

A mesoporous superparamagnetic iron oxide nanoparticle as a generic drug delivery system for tumor ferroptosis therapy

“…3 c). This partial lysosomal escape can be attributed to the release of Fe 2+ from MSPION3 under acidic condition, which leads to the conversion of intracellular H 2 O 2 into •OH through Fe 2+ catalysis, resulting in membrane damage [ 30 ]. The results of cellular uptake and lysosome escape demonstrate that our MSPION as a generic DDS can deliver SFN and BQR into tumor cells for anti-cancer therapy.…”

Inorganic nanoparticle agents for enhanced chemodynamic therapy of tumours

“…Recently, Wang et al developed ferritin heavy chain (FHC)-silencing siRNA-embedded iron (Fe 0 -siRNA) nanoparticles. 87 Upon internalization by tumour cells, the Fe 0 -siRNA nanoparticles degraded and released Fe 2+ and FHC-silencing siRNA within the acidic endo/lysosomes while consuming O 2 . On the one hand, the released FHC-silencing siRNA could escape the endo/lysosomes, as a result of CDT-induced cellular membrane disruption, and downregulate FHC to suppress the transformation of Fe 2+ to Fe 3+ , an ionic form that is known to be less CDT effective.…”

Autocatalytic Artesunate Coordinated ZIF-8 Nanoplatforms with Metal-Polyphenol Network Coating for Targeted Tumor Chemodynamic Therapy

“…5,6 Especially, mounting evidence demonstrated that ferrous ions-mediated CDT had great potential in tumor therapy due to high efficiency and low side effects. 7 However, the limited supply of hydrogen peroxide in tumor microenvironment severely impaired the curative effect of CDT. 8 Therefore, the development of hydrogen-peroxideindependent CDT is an urgent clinical need.…”

“…Chemodynamic therapy (CDT) is an emerging therapeutic strategy that produces excess free redicals via Fenton or Fenton-like reaction, resulting in irreversible oxidative damage to biological macromolecules. − Since it was first proposed in 2016, CDT is considered as a “Trojan Horse” therapeutic regimen that utilizes transition metal nanomedicine (such iron, copper, manganese, cobat) to react with endogenous hydrogen peroxide, finally producing the highly active free radicals which can be applied in the proliferative diseases treatment and antimicrobial infections. , Especially, mounting evidence demonstrated that ferrous ions-mediated CDT had great potential in tumor therapy due to high efficiency and low side effects . However, the limited supply of hydrogen peroxide in tumor microenvironment severely impaired the curative effect of CDT .…”