The successful treatment of osteomyelitis remains a great challenge in the field of orthopedics. The clinical method for treating refractory bone infection requires a combination therapy of long-term systemic antibiotics administration and surgical debridement. It is highly desirable to develop an antibiotic-free, noninvasive, rapid strategy to eradicate osteomyelitis. Herein, we fabricate a piezoelectric-enhanced sonosensitizer that consists of a porphyrin-based hollow metal-organic framework (HNTM), MoS nanosheets, and a red cell (RBC) membrane. We find that the ultrasound (US)-induced piezoelectric polarization of MoS can improve the charge transfer of HNTM at the heterointerface of HNTM-MoS, increasing the production of reactive oxygen species (ROS). Besides, MoS increases the asymmetric shape of HNTM, leading to the strong US-propelling ability of HNTM-MoS. The produced ROS and strong mechanical force can kill methicillin-resistant (MRSA) with an antibacterial efficiency of 98.5% under 15 min of US treatment, resulting in intracellular DNA damage and increased oxidative stress and disturbance of purine metabolism, tryptophan metabolism, and pantothenate and CoA biosynthesis of MRSA. Together with the toxin neutralization ability, the RBC-HNTM-MoS successfully eliminates the bone infection and suppresses inflammation and bone loss. This work provides another strategy for developing an efficient sonosensitizer through piezoelectric-assisted sonocatalysis and enhancing US-propelling ability.