Tumor Microenvironment-responsive Nanodrug for Clear-cell Renal Cell Carcinoma Therapy via Triggering Waterfall-like Cascade Ferroptosis

Abstract BackgroundThe most common type of kidney tumor, clear-cell renal cell carcinoma (ccRCC) with relatively insidious development and easily metastatic characteristics is generally insensitive to cytotoxic chemotherapy. Advanced ccRCC lacks effective treatment and has a poor prognosis. Fortunately, ccRCC with the hallmark of abundant polyunsaturated fatty acids (PUFAs) content is regarded as intrinsically vulnerable to ferroptosis-based therapeutic strategies. Nonetheless, the classic ferroptosis agonist (RSL3) with low specificity for tumors, short half-life in the blood, poor water solubility and deficient accumulation at the tumor site prevents its reliable application in vivo . ResultsIn this study, iron-based metal-organic framework nanoparticles (MIL-101(Fe) NPs) delivered RSL3 to ccRCC tumors, and then released the iron ions and RSL3 accompanied by the degradation of MIL-101(Fe) NPs in the acidic tumor microenvironment. The MIL-101(Fe)@RSL3 as a pH-responsive nanodrug causes cellular iron overload and promotes the hydroxyl radical (•OH) generation by Fenton reaction to attack PUFAs, leading to the aberrant accumulation of lipid peroxides (L-OOH). Additionally, RSL3 directly inhibits glutathione peroxidase 4 (GPX4) to detoxify L-OOH, and ferrous ions further catalyze the irreversible conversion of highly reactive lipid alkoxyl radicals (L-O•) from L-OOH to triggering waterfall-like cascade ferroptosis. In contrast to the limited antitumor efficiency of free RSL3, MIL-101(Fe)@RSL3 with high encapsulation efficiency (88.7%) shows a significant ccRCC-specific antitumor effect and negligible side effects.ConclusionMIL-101(Fe)@RSL3 could aggravate ferroptosis and be expected to be a promising nanodrug for ccRCC systemic therapy due to the targeted delivery and responsive release of RSL3 and iron ions.