Acute kidney injury (AKI) can be triggered by multiple insults, including ischemia–reperfusion, sepsis, and drug-induced nephrotoxicity. It is characterized by abrupt onset, rapid progression, and rapidly amplifying pathological cascades. Clinically, AKI often manifests as a reduced glomerular filtration rate, elevated serum creatinine or blood urea nitrogen, and oliguria; in severe cases, anuria may occur. Despite substantial heterogeneity in etiology, the pathological evolution of AKI converges on shared, therapeutically actionable hubs. Early microcirculatory dysfunction and an imbalance between oxygen supply and demand precipitate an energy crisis in renal tubules. Subsequent mitochondrial injury amplifies reactive oxygen species (ROS) and H2O2, creating a positive feedback loop with inflammatory and immune responses. Sustained oxidative stress and inflammation can trigger multiple cell death programs, such as apoptosis, necrosis, and ferroptosis. These processes result in epithelial barrier breakdown, tubular lumen obstruction, and rapid deterioration of renal function. If acute-phase injury is not promptly interrupted, persistent low-grade inflammation and chronic hypoxia may promote fibrotic remodeling, significantly increasing the long-term risk of AKI-to-CKD transition. In recent years, stimuli-responsive nanomaterials have been designed to exploit microenvironmental signals within AKI lesions, such as ROS/H2O2, pH, hypoxia, enzymes, and reductive molecules, as well as exogenous physical triggers such as ultrasound. These systems follow a paradigm of circulatory quiescence, lesion activation, and intracellular or organelle-targeted release/catalysis, thereby enabling spatiotemporally controlled therapy that balances effective renal exposure with minimal off-target effects. This review is guided by the key pathological hubs of AKI. It systematically summarizes structural designs and activation mechanisms of several types of responsive platforms. These include ROS/oxidative stress responsive systems such as TK, PBAP, and non-classical physicochemical state-switching or self-consuming platforms. They also encompass H2O2-activatable strategies such as gas-releasing, nanomotor, and nanozyme-based approaches with pathway-selective catalysis and visualization. Additional platforms include pH-responsive release, ultrasound-triggered carriers, and hypoxia-responsive systems. We further distill shared principles of stepwise activation in multi-stimulus synergistic systems. In these systems, tissue-level pH-mediated presentation and penetration are coupled with organelle-level ROS/H2O2-enabled therapeutic unlocking. Finally, we critically examine key translational challenges, including safety and biodegradability, dose windows, stratification by AKI subtype and disease course, endpoint evaluation frameworks, and scalability and batch-to-batch manufacturing consistency. These considerations provide a framework for the rational design and clinical translation of precision nanotherapeutics for AKI.
Chen et al. (Mon,) studied this question.