Administering a bio-lubricant is a promising therapeutic approach for the treatment of osteoarthritis (OA), in particular, if it can both manage symptoms and halt disease progression. However, the clearance of these bio-lubricants mediated by synovial macrophages leads to reduced therapeutic efficiency and adverse inflammatory responses. Herein, it is shown that this process is predominantly mediated by the specific binding of complement C3 (on nanoparticle) and CD11b (on macrophage). More importantly, through a systematic evaluation of various interface modifications, a macrophage-evading nanoparticle strategy is proposed, which not only minimizes friction, but also largely suppresses C3 adsorption. It involves employing a zwitterionic poly-2-methacryloyloxyethyl phosphorylcholine (PMPC) brush layer grafted from a crosslinked gelatin core. In vitro studies demonstrate that such a nanoparticle lubricant can evade macrophage phagocytosis and further prevent the pro-inflammatory M1 polarization and subsequent harmful release of cytokines. In vivo studies show that the designed PMPC brush layer effectively mitigates synovial inflammation, alleviates OA-associated pain, and protects cartilage from degeneration, thus preventing OA progression. These findings clarify the pivotal role of complement C3-mediated macrophage recognition in nanoparticles clearance and offer a promising nanoparticle design strategy to restore joint lubrication.