Persistent and intense inflammation is recognized as the primary cause of wear-particle-induced aseptic osteolysis, which ultimately resulting in aseptic prosthesis loosening. Reducing inflammation plays a significant role in mitigating osteolysis, and the STING pathway has emerged as a promising therapeutic target for its prevention. Specifically, damaged periprosthetic cells of aseptic osteolysis release double-stranded DNA (dsDNA) into the osteolytic microenvironment, serving as a specific stimulus for the STING pathway. Herein, we found that layered double hydroxide (LDH) nanozyme exhibited a robust DNA-binding capacity primarily mediated by van der Waals interactions, which showed superior performance in inhibiting dsDNA-induced inflammation of aseptic osteolysis. Importantly, such binding capability enabled effective co-loading LDH with STING inhibitor C176, thus facilitating inhibition of the STING pathway. Such synergistic actions contributed to ameliorate the inflammatory milieu and remodel the osteolysis microenvironment successfully to reduce cranial bone damage, which was confirmed on animal model of osteolysis. Collectively, this strategy demonstrated an effective approach by utilizing synergistic effects to establish a positive feedback loop in the treatment of osteolysis, thereby alleviating TiPs-induced periprosthetic osteolysis and preventing postoperative complications.