Tetrahedral DNA Nanoframework‐Based Multivalent Aptamers Functionalized Biomimetic Hydrogel Scaffold Enhances Osteochondral Regeneration by Recruitment and Protection of Endogenous Stem Cells

Abstract The recruitment of endogenous stem cells is crucial for in‐situ tissue regeneration, especially for addressing the limited self‐repair capacity of bone and cartilage. However, the recruited stem cells are vulnerable to damage from oxidative stress, leading to a loss of differentiation potential. Here, a well‐designed strategy is presented for osteochondral defect repair that enhances endogenous stem cell recruitment, protection, and differentiation. Multivalent DNA aptamers are created by conjugating DNA tetrahedral with a stem cell‐specific aptamer, Apt19s, to improve stem cell binding and migration in vivo. Additionally, icariin and epigallocatechin gallate are respectively inserted into the double strands of the PolyApt, resulting in ATI and ATE, which effectively scavenge reactive oxygen species, protect stem cells from oxidative stress, and promote the differentiation of chondrocytes and osteoblasts. Furthermore, a degradable gradient hydrogel scaffold based on gelatin methacryloyl and poly(ethylene glycol) diacrylate is fabricated, with ATI in the upper layers and ATE in the bottom layers, to provide early mechanical support and enhance tissue regeneration upon scaffold degradation. Overall, the approach of recruiting, protecting, and guiding the specific differentiation of endogenous stem cells represents a universal strategy for in‐situ tissue regeneration, offering significant potential for clinical translation.