Polyacrylic Acid‐Coated Selenium‐Doped Carbon Dots Inhibit Ferroptosis to Alleviate Chemotherapy‐Associated Acute Kidney Injury

Abstract Cisplatin‐associated acute kidney injury (AKI) is a severe clinical syndrome that significantly restricts the chemotherapeutic application of cisplatin in cancer patients. Ferroptosis, a newly characterized programmed cell death driven by the lethal accumulation of lipid peroxidation, is widely reported to be involved in the pathogenesis of cisplatin‐associated AKI. Targeted inhibition of ferroptosis holds great promise for developing novel therapeutics to alleviate AKI. Unfortunately, current ferroptosis inhibitors possess low bioavailability or perform non‐specific accumulation in the body, making them inefficient in alleviating cisplatin‐associated AKI or inadvertently reducing the anti‐tumor efficacy of cisplatin, thus not suitable for clinical application. In this study, a novel selenium nanomaterial, polyacrylic acid‐coated selenium‐doped carbon dots (SeCD), is rationally developed. SeCD exhibits high biocompatibility and specifically accumulates in the kidney. Administration of SeCD effectively scavenges broad‐spectrum reactive oxygen species and significantly facilitates GPX4 expression by releasing selenium, resulting in strong mitigation of ferroptosis in renal tubular epithelial cells and substantial alleviation of cisplatin‐associated AKI, without compromising the chemotherapeutic efficacy of cisplatin. This study highlights a novel and promising therapeutic approach for the clinical prevention of AKI in cancer patients undergoing cisplatin chemotherapy.

ToloScript All-in-one RT EasyMix for qPCR (22107) was purchased from Tolo Biotech.

Figure S2 .
Figure S2.SeCD accumulates in the kidneys and is gradually cleared over time.(a) The selenium contents in the kidneys isolated from mice after 1, 3, 7, 14, and 30 days of single SeCD intravenous injection (0.5 mg/kg bodyweight) were determined by LC-AFS.All data are presented as mean ± SD (n = 4).Statistical significance was calculated using an unpaired two-tailed Student's t-test.* P < 0.05.

Figure S4 .
Figure S4.SeCD attenuates cell death in primary renal tubules.The primary renal tubules were treated with 20 μM CP with or without 6 mg/L SeCD for 24 h.PI staining was used to visualize cell death.Scale bar: 100 μm.

Figure S5 .
Figure S5.SeCD enters cultured cells rapidly.(a) HK-2 cells were incubated with the indicated doses (1, 2, and 3 mg/L) of SeCD for 4 h.The nuclei were labelled with DAPI.SeCD fluorescence is green.Confocal images showed SeCD uptake.Scale bar: 60 μm.(b, c) Cells were treated as in (a).Flow cytometry analysis was performed to show SeCD uptake (b), and the relative MFI was quantified (c).(d) HK-2 cells were incubated with 2 mg/L SeCD for the indicated time.The nuclei were labelled with DAPI.SeCD fluorescence is green.Confocal images showed SeCD uptake.Scale bar: 60 μm.(e, f) Cells were treated as in (d).Flow cytometry analysis was used to determine SeCD uptake (e), and the relative MFI was quantified (f).All data are expressed as mean ± SD (n = 3).Statistical significance was calculated using one-way ANOVA.*** P < 0.001.

Figure S7 .
Figure S7.SeCD resists RSL3-and erastin-induced lipid peroxidation and preserves mitochondrial integrity.(a, b) HK-2 cells were treated with 1 μM RSL3 for 4 h (a) or 10 μM erastin for 24 h (b) in the presence or absence of 6 mg/L SeCD.The intracellular MDA levels were determined.(c, d) HK-2 cells were treated as in (a) and (b).Confocal images showed DHE staining in each group.Scale bar: 30 μm. (e, f) HK-2 cells were treated as in (a) and (b).The cells were fixed and stained with an anti-8-OHdG antibody.Representative confocal images were shown.Scale bar:

Figure S9 .
Figure S9.SeCD administration does not reduce the chemotherapeutic efficacy of cisplatin.(a) Representative H&E staining of tumors isolated from each group of mice.Scale bar: 200 μm.(b) Representative TUNEL staining in the tumors.Scale bar: 200 μm.(c) Immunofluorescence staining of Ki-67 in the tumors.The nuclei were stained with DAPI.Scale bar: 200 μm.

Figure S10 .
Figure S10.SeCD does not enrich in the xenograft tumors.The selenium contents in the xenograft tumors isolated from each group of mice were determined by LC-AFS.All data are presented as mean ± SD (n = 5-6).Statistical significance was calculated using an unpaired twotailed Student's t-test.ns P > 0.05.