<p>Although reactive oxygen species (ROS)-based antibiofilm therapy has emerged as a promising nonantibiotic approach, its therapeutic efficacy remains limited by the short lifetime and restricted diffusion of ROS as well as the intrinsic barriers of biofilms. Here, we designed a bacteria-targeted piezoelectric heterostructure (U-B/F) composed of boronic acid-functionalized UiO-66(Hf) (U-B) and carboxylated fullerene (C₇₀-COOH) for synergistic biofilm eradication. The boronic acid groups enabled selective bacterial binding, while the ultrasound (US)-activated Z-scheme heterojunction strengthened the piezoelectric response and enhanced charge separation, thereby amplifying sonocatalytic ROS generation. In parallel, fullerene acted as a peroxidase-mimetic catalyst, converting endogenous H₂O₂ into highly cytotoxic hydroxyl radical (•OH). Beyond ROS pathways, the favorable band alignment allowed US-induced electron transfer from bacteria to U-B/F, thereby interfering with bacterial electron transport and energy metabolism. Transcriptomic profiling revealed molecular signatures of bioenergetic collapse and oxidative stress. Functionally, this strategy achieved 99.99% elimination of planktonic methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and 92.41% removal of mature biofilms <i>in vitro</i>. In MRSA-infected diabetic mice, U-B/F under US irradiation significantly accelerated wound healing by eradicating infection, alleviating inflammation, and promoting tissue regeneration. Overall, this work provides a rational strategy for designing multifunctional nanomaterials that integrate bacterial targeting, dual ROS catalysis, and US-induced electron transfer interference to combat biofilm-associated infections.</p>