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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 however, the unique renal vasculature architecture delivers a very limited oxygen supply to the renal tubules. Hypoxia is a critical mediator in kidney diseases worldwide, which plays a pivotal role in the initiation and progression of both acute kidney injury (AKI) and chronic kidney disease (CKD). Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs. This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. 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. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation.
YU FENG XING PC
In 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 α 4β 1 and α Lβ 2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly 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). 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. Hypoxia is a major contributor to global kidney diseases.