Osteoarthritis involves complex inflammatory responses, leading to cell death and joint dysfunction. Key contributors are pro-inflammatory molecules, such as excess reactive oxygen species (ROS) and cell-free DNA (cfDNA), which require effective scavenging. Concurrently, delivering anti-inflammatory agents can stimulate immune cells to restore tissue repair by resolving inflammation. Thus, a “push-and-pull” approach-combining delivery and scavenging-is optimal for osteoarthritis treatment. Here, we propose a multitherapeutic strategy using polycationic-functionalized mesoporous ceria nanoparticle (mCNP-G) to target osteoarthritic joint cartilage. The mCNP core, with its multiple catalytic capabilities and mesoporous structure, was effective in scavenging ROS and loading/releasing the anti-inflammatory drug dexamethasone. Additionally, polycationic functionalization enhanced the scavenging of cfDNA released from damaged or dying cells. These combined functions of mCNP-G substantially down-regulated pro-inflammatory signaling, thereby rescuing cells and interrupting the inflammatory feedback loop. Moreover, mCNP-G demonstrated high affinity for cartilage tissue, facilitating targeted retention to osteoarthritis region. When locally administered to rat osteoarthritic temporomandibular joint, mCNP-G with dexamethasone significantly reduced cfDNA and oxidative stress, inhibited inflammation, and salvaged cells, ultimately alleviating osteoarthritic symptoms and osteochondral damage. This nanomedicine offers a promising therapeutic strategy for osteoarthritis by integrating the push-and-pull functions of drug delivery and ROS/cfDNA dual-scavenging within a single system.