Nano‐networks via reaction‐induced self‐assembly coordinate spatiotemporal multi‐drug delivery for acute kidney injury therapy

Abstract Acute kidney injury (AKI) is a severe disease driven by a vicious cycle of tubular damage, oxidative stress, and inflammation, yet current therapies remain limited by poor targeting, short bioavailability, and inability to synergistically regulate multiple pathological pathways. To address this, we develop multifunctional nano‐networks (NNWs) through reaction‐induced self‐assembly of spermidine, epigallocatechin gallate, 2‐formylphenylboronic acid, and deferoxamine via dynamic iminoboronate bonds. These NNWs exploit the oxidative AKI microenvironment to trigger disintegration, thereby enabling the site‐specific release of therapeutic agents. Deferoxamine and epigallocatechin gallate chelate excess iron to suppress ferroptosis‐associated apoptosis, while epigallocatechin gallate and spermidine synergistically mitigate oxidative stress and inflammation through reactive oxygen species scavenging, autophagy promotion, and cytokine inhibition. NNWs overcome the limitations of single‐drug therapy or physically combined drug therapy by integrating targeted delivery, controlled release, and multi‐pathway modulation, thereby disrupting the self‐perpetuating injury cycle. In vitro and in vivo evaluations demonstrated enhanced renal accumulation and superior efficacy in alleviating AKI pathology. This platform provides a promising strategy for spatiotemporally coordinated AKI treatment, offering a blueprint for combinational nanotherapies in complex disease settings.