NIR-II triggered HSP70 activation by Cu_2–XSe complex epimedium disrupts inflammatory cascade for targeted therapy of acute kidney injury

Acute kidney injury (AKI) has high incidence and mortality rates, with its vicious cycle involving inflammation, oxidative stress, and apoptosis often leading to rapid decline in renal function. Current treatments face multiple challenges: lack of targeted drugs, limited efficacy of conventional therapies with significant systemic side effects, difficulty in drug delivery to the kidney's unique structure, susceptibility to re-injury, rapid disease progression, a narrow intervention window, and high risk of irreversible damage. To address these issues, we developed the near-infrared II (NIR-II)-excited photothermal nanocomposite Cu_2–XSe@AHI. Constructed via coordination self-assembly, this material offers advantages of structural controllability, spatiotemporal precision, and non-invasive treatment. Upon NIR-II laser activation, it achieves deep tissue penetration and low-toxicity photothermal conversion, generating mild thermal stimulation in the kidney to specifically induce heat shock protein 70 (HSP70) expression. HSP70 stabilizes the inhibitor of κB alpha–IκB kinase beta (IκBα–IKKβ) complex, inhibiting the nuclear factor kappa-B (NF-κB) pathway to synergistically exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Furthermore, HSP70 upregulation enhances cellular resilience and promotes tissue repair, enabling a dual mechanism from injury blockade to active restoration. This strategy overcomes limitations of existing therapies, offering a novel pathway with high translational potential for AKI treatment.