The high demand for acute kidney injury (AKI) therapy calls for the development of new therapeutics for renal management. Oxidative stress, coupled with excessive inflammation, is the main pathological mechanism for AKI. Specifically, complement component 5a (C5a) exacerbates the vicious cycle between oxidative stress and inflammatory responses. Herein, we developed a cascade-functioning mirror-image DNA nanostructure, L-DNA tetrahedron (LDT), for sequentially blocking the extracellular complement C5a to alleviate inflammation and eliminating intracellular reactive oxygen species (ROS) to inhibit oxidative stress. A C5a-neutralizing mirror-image aptamer (LA) was incorporated into LDT via a ROS-sensitive linker (thioketal, i.e., TK bond), which enabled the release of LA in the inflammatory microenvironment to block C5a. LA-conjugated LDT (LDT-LA) exhibited preferential renal uptake and enhanced renal retention compared with its counterpart made of D-nucleic acids and provided effective treatment in ischemia-reperfusion (I/R)-, cisplatin-, and glycerol-induced AKI mouse models. Meanwhile, LDT-LA exhibits excellent biocompatibility, making it a promising candidate for AKI therapy. The biostable, cascade-functioning LDT-LA could act as a multifunctional platform for the treatment of other diseases by conjugating with appropriate functional groups.

Angew. Chem. Int. Ed. 2026, e4575346 https://onlinelibrary.wiley.com/doi/10.1002/anie.4575346