Inflammation-primed extracellular vesicles achieve dual optimization of membrane targeting and therapeutic cargo for precision therapy against acute kidney injury

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Abstract Title *

Inflammation-primed extracellular vesicles achieve dual optimization of membrane targeting and therapeutic cargo for precision therapy against acute kidney injury

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Co-author 1

Chuyue Zhang zhangcycywch@wchscu.edu.cn West China Hospital Department of Nephrology Chengdu China *

Co-author 2

Liang Ma Liang_m@scu.edu.cn West China Hospital Department of Nephrology Chengdu China -

Co-author 3

Ping Fu Fupinghx@scu.edu.cn West China Hospital Department of Nephrology Chengdu China -

Co-author 4

Zhiyong Qian zhiyongqian@scu.edu.cn West China Hospital State Key Laboratory of Biotherapy Chengdu China -

Co-author 5

Xiangmei Chen xmchen301@126.com First Medical Center of Chinese PLA General Hospital Department of Nephrology Beijing China -

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Introduction

Acute kidney injury (AKI) remains a clinical challenge lacking effective pharmacotherapies, with mutually exacerbating inflammation and oxidative stress driving disease progression. While mesenchymal stem cell-derived extracellular vesicles (EVs) possess intrinsic anti-inflammatory and pro-regenerative properties, their clinical potential is hindered by non-specific delivery and insufficient payloads. Here, we developed a dual-optimization strategy to engineer EVs into a precision smart platform with kidney-specific targeting and a potent therapeutic cargo.

Methods

We first generated inflammation-educated EVs (pEVs) via a single-step priming that simultaneously enriches the vesicles with both surface integrin α4β1 for targeting and an increased therapeutic miRNA payload. These pEVs were subsequently conjugated to the mitochondrial antioxidant SS31 via a reactive oxygen species (ROS)-cleavable thioketal (TK) linker to yield pEV‑TK‑SS31. Targeting and therapeutic mechanisms were validated using in vivo imaging, adeno-associated virus-mediated gene knockdown, miRNA profiling, lentiviral rescue experiments, and immunohistochemistry of human AKI biopsy specimens.

Results

Inflammation priming induced membrane integrin α4β1, enabling targeted binding to its ligand, vascular cell adhesion molecule-1 (VCAM‑1) which is upregulated in inflamed renal tissue. Concurrently, this strategy enriched the cargo with miR-146a-5p, which suppresses TNF receptor–associated factor 6 (TRAF6), a proinflammatory signaling hub upregulated in the kidneys of AKI patients. In parallel, elevated ROS at sites of renal injury cleaved the TK linker to trigger localized release of SS31; the liberated SS31 then cooperated with the intrinsic pEV cargo to disrupt the inflammation–oxidative stress feedback loop. This dual-action mechanism conferred robust renoprotection across three distinct AKI models: ischemia-reperfusion, sepsis-induced, and cisplatin-induced.

Conclusion

This upstream dual-optimization strategy, driven by streamlined cell conditioning, co-integrates lesion-specific targeting with therapeutic payload enhancement onto a single platform, thereby amplifying anti-inflammatory and anti-oxidative effects to effectively mitigate the core pathological processes of AKI.

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