ROS-responsive cellular vesicles with ferroptosis-targeting siACMSD delivery for acute kidney injury therapy.

Area of Science:

• Nephrology
• Biochemistry
• Biotechnology

Background:

• Acute kidney injury (AKI) is a prevalent condition lacking effective treatments.
• Alpha-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) exacerbates AKI by affecting the TCA cycle and NAD+ production.
• Current strategies for ACMSD-targeted therapy are limited.

Purpose of the Study:

• To investigate the therapeutic potential of ACMSD inhibition in AKI.
• To explore the role of ACMSD in ferroptosis during AKI.
• To develop an efficient drug delivery system for ACMSD-targeted AKI therapy.

Main Methods:

• ACMSD knockout was performed using CRISPR-Cas9 in vitro.
• Reactive oxygen species (ROS)-responsive neutrophil-derived cellular vesicles (CVs) encapsulating RNAi (RNAi@ROS-CVs) were developed for in vivo ACMSD knockdown.
• Mice models of cisplatin-induced and ischemia/reperfusion (I/R)-induced AKI were utilized.

Main Results:

• ACMSD knockout in HK2 cells reduced mitochondrial damage, suppressed the TCA cycle, enhanced NAD+ synthesis, and inhibited ferroptosis.
• RNAi@ROS-CVs effectively targeted injured kidneys in mice, downregulating ACMSD expression.
• Treatment reduced ROS production, lipid peroxidation, and alleviated ferroptosis in AKI models.

Conclusions:

• ACMSD-targeted knockout presents a viable therapeutic strategy for AKI.
• The developed RNAi@ROS-CVs platform offers an efficient, controlled-release drug delivery system for AKI.
• This approach holds potential for treating other acute renal diseases.