ObjectIschemia‐reperfusion (I/R)‐induced acute renal injury has become a serious issue in clinical. The increasingly mortality, induced by chronic fibrosis and further renal dysfunction which caused by poor recovery of acute injury, has made it urgent to address kidney tissue repair. By using a renal I/R injury model, we aimed to investigate the role of a hydrogel‐based dual‐drug delivery platform on promoting tissue repair.MethodsAn injectable, self‐assembling peptide/heparin (SAP/Hep) hydrogel was employed to co‐deliver TNF‐α neutralizing antibody (anti‐TNF‐α) and hepatocyte growth factor (HGF). We analyzed the microstructure and controlled release properties of KLD2R/Hep hydrogel in vivo. The effects of the drug‐loaded hydrogel (SAP‐drug) on renal injury were evaluated in a rodent renal I/R injury model.ResultsIn vitro, the SAP/Hep hydrogel exhibited a faster release of anti‐TNF‐α with a sustained release of HGF, and both drugs could maintain better bioactivities after release. In vivo, combined anti‐TNF‐α/HGF showed better renal protective potential than anti‐TNF‐α or HGF alone. Compared with free‐drug (anti‐TNF‐α/HGF in solution) or SAP alone , SAP‐drug treatment significantly reduced the levels of serum creatinine (Scr)/blood urea nitrogen (BUN), tubular apoptosis, renal inflammatory factors and macrophage infiltration. Moreover, the SAP‐drug group exhibited better efficacy on promoting tubular cell proliferation and dedifferentiation than SAP or free‐drug alone, and thus reduced chronic renal fibrosis in I/R injury mice.ConclusionsWe confirmed that SAP could sequentially deliver anti‐TNF‐α and HGF to achieve anti‐inflammatory and pro‐proliferative effects simultaneously with only once injection, and thus can be a promising delivery platform for tissue repair.Support or Funding InformationThis work was supported by grants from National Natural Science Foundation of China (81571808, 31871001, 31200754) and Sichuan Science and Technology Program (2019YJ0069)Design of dual‐drug delivery KLD2R/Hep hydrogel for enhancing renal repair. The formation of the cationic KLD2R/anionic heparin hybrid hydrogel via electrostatic interaction, and heparin further had high affinity to HGF. The encapsulated anti‐TNF‐α and HGF were released from hydrogel in a sequential manner, and thus synergistically promoted tissue repair.Figure 1