A novel mesenchymal stem cell-targeting dual-miRNA delivery system based on aptamer-functionalized tetrahedral framework nucleic acids: Application to endogenous regeneration of articular cartilage.

Articular cartilage injury (ACI) remains one of the key challenges in regenerative medicine, as current treatment strategies do not result in ideal regeneration of hyaline-like cartilage. Enhancing endogenous repair via microRNAs (miRNAs) shows promise as a regenerative therapy. miRNA-140 and miRNA-455 are two key and promising candidates for regulating the chondrogenic differentiation of mesenchymal stem cells (MSCs). In this study, we innovatively synthesized a multifunctional tetrahedral framework in which a nucleic acid (tFNA)-based targeting miRNA codelivery system, named A-T-M, was used. With tFNAs as vehicles, miR-140 and miR-455 were connected to and modified on tFNAs, while Apt19S (a DNA aptamer targeting MSCs) was directly integrated into the nanocomplex. The relevant results showed that A-T-M efficiently delivered miR-140 and miR-455 into MSCs and subsequently regulated MSC chondrogenic differentiation through corresponding mechanisms. Interestingly, a synergistic effect between miR-140 and miR-455 was revealed. Furthermore, A-T-M successfully enhanced the endogenous repair capacity of articular cartilage in vivo and effectively inhibited hypertrophic chondrocyte formation. A-T-M provides a new perspective and strategy for the regeneration of articular cartilage, showing strong clinical application value in the future treatment of ACI.