Osteoarthritis (OA) is one of the most common joint degenerative diseases without effective treatment, whose pathology is related to the local accumulation of senescent cells (SnCs). However, existing SnCs-scavenging drugs "senolytics" may lead to the exhaustion of stem and progenitor cells, impairing chondrocyte proliferation and cartilage regeneration. Here, ADAM19, a kind of endopeptidases from the ADAM (a disintegrin and metalloproteinase) family, is identified as a novel target for senescent chondrocyte rejuvenation. ADAM19 is elevated in senescent chondrocytes in both mice and human osteoarthritic joints, as well as in cellular senescence model in vitro. ADAM19 knockdown not only significantly attenuated senescent phenotype of chondrocytes, but also promoted cell proliferation and extracellular matrix synthesis. RNA sequencing revealed ADAM19 may regulate chondrocyte senescence mainly through the PI3K/AKT signal axis. In addition, a senescence-targeting small interfering RNA (siRNA) delivery system is developed for in vivo delivery of therapeutic siRNA. The complex selectively released ADAM19 siRNA in SnCs and performed high silencing effect on target gene. Furthermore, intra-articular (IA) injection of the complex once every two weeks in OA mice effectively reduced SnCs accumulation and promoted hyaline cartilage regeneration. This study provides a promising strategy for the development of regenerative RNA interference therapy.