Optimization of M1 macrophage targeting using a glucosylated albumin nanoplatform for ROS scavenging and mitochondrial rescue in acute kidney injury

TL;DR

A new nanoplatform targets M1 macrophages to reduce kidney injury by scavenging harmful molecules and protecting mitochondria.

Contribution

A glucosylated albumin nanoplatform that specifically targets M1 macrophages to mitigate oxidative stress and mitochondrial dysfunction in acute kidney injury.

Findings

Glc6-AD11-Alb selectively targets M1 macrophages and reduces intracellular reactive oxygen species in vitro.

In vivo administration of Glc6-AD11-Alb attenuates renal dysfunction and promotes tubular regeneration in ischemia–reperfusion injury models.

The nanoplatform restores mitochondrial membrane potential and improves mitochondrial bioenergetics in renal tubular epithelial cells.

Abstract

Acute kidney injury (AKI) remains a major clinical challenge resulting from the intertwined processes of oxidative stress and macrophage-driven inflammation, both converging on mitochondrial dysfunction. We developed a glucosylated albumin nanoplatform (Glc6-AD11-Alb) designed to exploit glucose transporter 1-mediated uptake in inflammatory M1 macrophages while preserving the intrinsic antioxidant properties of albumin.

Physicochemical characterization confirmed reproducible synthesis with defined degrees of functionalization and stable physicochemical properties. In vitro, Glc6-AD11-Alb demonstrated selective uptake in M1 macrophages and significantly reduced intracellular reactive oxygen species, validating its dual role in immune modulation and redox regulation. Positron emission tomography imaging with Cu-64 radiolabeling revealed preferential renal accumulation in ischemia–reperfusion injury (IRI) models, supporting macrophage-targeted delivery. In vivo, administration of Glc6-AD11-Alb attenuated renal dysfunction, suppressed pro-inflammatory and oxidative markers, and promoted tubular regeneration in pre- and post-treatment settings. Importantly, Glc6-AD11-Alb directly protected renal tubular epithelial cells by restoring mitochondrial membrane potential under oxidative and hypoxic stress. Seahorse metabolic flux analysis further confirmed enhanced oxidative phosphorylation, reduced glycolytic dependency, and improved coupling efficiency, indicating recovery of mitochondrial bioenergetics. Transmission electron microscopy demonstrated preservation of mitochondrial ultrastructure, including intact cristae and elongated morphology, consistent with improved ATP synthesis capacity.

Glc6-AD11-Alb acts through complementary mechanisms of macrophage-targeted immune modulation and mitochondrial protection, thereby disrupting the vicious cycle of inflammation and oxidative stress in AKI. This nanoplatform represents a clinically translatable therapeutic strategy with potential to improve outcomes in patients with ischemic kidney injury.

The online version contains supplementary material available at 10.1186/s12951-026-04061-6.

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