Osteoarthritis (OA), a degenerative joint disease, is characterized by chondrocyte senescence, extracellular matrix (ECM) degradation, and chronic inflammation, with limited regenerative capacity. Current therapies primarily provide symptom relief, therefore highlighting the need for more effective strategies to address OA's multifactorial pathology. This study introduces an innovative selenium nanozyme-crosslinked injectable composite hydrogel (Se/PRP-OGel), which combines selenium nanoparticles (SeNPs) with platelet-rich plasma (PRP) in a biocompatible oxidized chondroitin sulfate-gelatin scaffold (OGel), to address OA through an integrated "outside-in" and "inside-out" strategy. The "outside-in" strategy utilizes SeNPs to scavenge reactive oxygen species (ROS), alleviate oxidative stress, and restore redox balance, thereby reducing extracellular damage and modulating inflammation in the OA microenvironment. Concurrently, the "inside-out" strategy utilizes PRP's bioactive growth factors (e.g., TGF-β, IGF, FGF) to rejuvenate senescent chondrocytes, stimulate proliferation, and enhance ECM synthesis, creating a regenerative microenvironment. The results showed that Se/PRP-OGel demonstrated excellent biocompatibility, reduced ROS levels, mitigated chondrocyte senescence, and balanced ECM homeostasis. Moreover, it promoted cartilage repair, pain relief, and functional restoration in an OA rat model. This dual approach interrupts OA's degenerative cycle and fosters cartilage regeneration, providing a groundbreaking solution for effective cartilage regeneration and OA treatment.Copyright © 2025 Elsevier Inc. All rights reserved.