Renal Clearable Ultrasmall Single-Crystal Fe Nanoparticles for Highly Selective and Effective Ferroptosis Therapy and Immunotherapy

Abstract

Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe 3 O 4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bcc-USINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.

A “Closed‐Loop” Therapeutic Strategy Based on Mutually Reinforced Ferroptosis and Immunotherapy

“…To determine the catalytic performance systematically, a steady-state kinetic analysis was detected. [31] (33,65,98,131 and 163 × 10 −3 m) were added to IS NPs (200 µg mL −1 ), CS NPs (200 µg mL −1 ) and CISAR NPs (200 µg mL −1 ) in the presence of TMB, and the time-dependent and H 2 O 2 concentration-dependent absorbance (652 nm) were measured (Figure S11a-f, Supporting Information). Then, the initial reaction rate was determined by the Beer-Lambert law, and the corresponding H 2 O 2 concentration curves were plotted and fitted using Michaelis-Menten saturation curves (Figure S11g-i, Supporting Information and Equation 1).…”

“…To determine the catalytic performance systematically, a steady‐state kinetic analysis was detected. [ 31 ] First, Fe in IS NPs comes from FeSO 4 ·7H 2 O (0.75 × 10 −3 m ), Cu in CS NPs (copper silicate) is from CuSO 4 ·3H 2 O (0.75 × 10 −3 m ), Cu and Fe in CIS NPs are from 0.25 × 10 −3 m CuSO 4 ·3H 2 O and 0.5 × 10 −3 m FeSO 4 ·7H 2 O, respectively. Various concentrations of H 2 O 2 (33, 65, 98, 131 and 163 × 10 −3 m ) were added to IS NPs (200 µg mL −1 ), CS NPs (200 µg mL −1 ) and CISAR NPs (200 µg mL −1 ) in the presence of TMB, and the time‐dependent and H 2 O 2 concentration‐dependent absorbance (652 nm) were measured (Figure S11a–f, Supporting Information).…”

Utilization of metal or non-metal-based functional materials as efficient composites in cancer therapies

“…Liang et al synthesized ultrasmall single-crystal Fe NPs (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of a Fe 3 O 4 shell and the exposure of the Fe (0) core. 49 The bcc-USINPSs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. The process of immunotherapy is shown in Fig.…”

Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM

“…IFN-γ secreted by activated T eff cell inhibits the cysteine transporter (xCT) and subsequently prevents the cysteine from being taken up by cancer cells, resulting in the reduction of GSH synthesis in cancer cells. Then, ferroptosis is significantly enhanced in turn [ 24 – 26 ]. In theory, ferroptosis inducer and PD-1/PD-L1 inhibitor can mutually enhance each efficacy when they are simultaneously used to treat GBM.…”