Osteoarthritis (OA) is a prevalent chronic inflammatory disease in joints. Current interventions confront systemic toxicity and insufficient bioavailability. The unbalanced microenvironment of OA joints mainly fosters over-expressed reactive oxygen species (ROS), extracellular matrix disintegration, and apoptosis of chondrocytes. In this study, a kind of ROS-scavenging, biodegradable and drug-free nanoparticles (PP NPs) were constructed by the crosslinking of poly(propylene fumarate) (PPF) and ROS-scavenging poly(thioketal) (PTK). The high content of PTK and high crosslinking density of PPF and PTK innovatively endowed the NPs with slow degradation and prolonged ROS-elimination ability. The NPs were further surface-modified with chondroitin sulfate (CS), one of the dietary supplements for osteoarthritis. The intrinsic properties of resultant PP-CS NPs were excavated in vitro and in vivo. The PP-CS NPs could desirably consume 1,10-diphenyl-2-picrylhydrazyl (DPPH) radicals without toxicity to RAW264.7 cells in vitro. With an average diameter of ~ 300 nm, the PP-CS NPs could be intra-articular administrated in OA rats and showed prolonged joint retention time, allowing only one injection per month. Moreover, the PP-CS NPs possessed a prolonged ROS depletion and M2 macrophage induction effect, down-regulated inflammatory cytokines, and reduced glycosaminoglycans loss. Consequently, the PP-CS NPs protected articular surface erosion, inhibited uneven cartilage matrix, and attenuated OA progression.