Abstract
BackgroundHypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs).ResultsIn murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4β1 and αLβ2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects.ConclusionThis synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.Graphical
Highlights
Hypoxia is a major contributor to global kidney diseases
Synthesis and characterization of the hypoxia‐sensitive Pc/ C5A complex We designed the hypoxia‐sensitive azocalixarene C5A based on the negative charge characteristic of Mesenchymal stem cells (MSCs)-extracellular vesicles (EVs)
The C5A design is well suitable for our purpose due to the following reasons: First, it is ready to be embedded into mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs) membranes as a cationic amphiphile through hydrophobic and electronic interactions
Summary
Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising thera‐ peutic option against both acute kidney injury and chronic kidney disease; an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Due to the drastic reabsorption and excretion processes that occur in the renal tubules, especially in proximal tubular epithelial cells (TECs), the maximum oxygen demand of the kidneys is second only to the brain [3]; the unique renal vasculature architecture delivers a very limited oxygen supply to the renal tubules [3, 4]. This prominent conflict between low supply and high demand makes TECs extremely vulnerable to hypoxic injury [5, 6]. To ameliorate renal hypoxia, a strategy that is able to fulfill simultaneous noninvasive imaging and targeted therapy is highly desirable but challenging
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