Biomimetic 7-dehydrocholesterol nanovehicles: a drug-free strategy for ferroptosis suppression in renal ischemia-reperfusion injury

Abstract

Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) triggers ferroptosis through oxidative stress and lipid peroxidation, exacerbating renal cell and tissue damage. 7-Dehydrocholesterol (7-D) was a pro-cholesterol molecule with a unique conjugated 5,7-diene structure that inhibits lipid peroxidation by trapping excessive radicals, thereby attenuating ferroptosis. However, direct administration of 7-D demonstrated limited efficacy in treating AKI. Here, we incorporated 7-D as the anti-ferroptotic agent and prepared it into liposomes (7-D@Lip) for the treatment of AKI. In addition, we added adenosine triphosphate (ATP) into the hydrophilic core of liposomes (7-D@A-Lip) to promote the uptake efficiency by damaged kidney cells. To enhance the distribution and accumulation of 7-D@A-Lip in the injured kidney, we extruded the renal cell membrane into the prepared liposomes (7-D@A-mLip). The results showed that 7-D@A-mLip could be rapidly internalized by hypoxia/reoxygenation-damaged renal cells, effectively inhibiting lipid peroxidation and alleviating ferroptosis-related injury. In addition, post-injection 7-D@A-mLip specifically accumulated in the renal tissues, reduced lipid hydroperoxide production by scavenging reactive oxygen species, and suppressed ferroptosis in the kidney, thereby preserving renal function in the AKI model. This study presented a promising renal-targeted delivery strategy for 7-D to mitigate ferroptosis in kidney disease.