The development of temporomandibular joint (TMJ) osteoarthritis is highly associated with mechanical overloading, which can result in accelerated cartilage degradation and damage due to increased interfacial friction and the release of inflammatory factors and catabolic enzymes. In the present study, we for the first time developed self-assembled drug-free nanospheres with pharmaceutical-active functions, which could be used as an intra-articularly injected biolubricant for the treatment of TMJ osteoarthritis based on a synergistic therapy of enhanced lubrication, anti-inflammation, and antisenescence. The nanospheres possessed the hydrophobic core of dopamine methacrylamide and the hydrophilic shell of sulfobetaine methacrylate, which formed into spherical aggregates in aqueous solution by specific interactions following reversible addition-fragmentation chain transfer polymerization. The biodegradation test, tribological test, and free radical scavenging test showed that the nanospheres were endowed with physiological stability, lubrication enhancement, and free radical scavenging capability. In addition, the in vitro cell test revealed that the nanospheres alleviated inflammatory and senescent phenotype for inflammation and oxidative stress stimulated chondrocytes. Furthermore, the in vivo animal test indicated that the nanospheres, after intra-articular injection into TMJ with an osteoarthritis environment, effectively protected condylar cartilage and subchondral bone from structural damage and attenuated cartilage matrix degradation and aging. In summary, the self-assembled nanospheres might be used as a promising biolubricant for achieving anti-inflammatory and antisenescent treatment of TMJ osteoarthritis.