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 piezoelectricenhanced sonosensitizer that consists of a porphyrin-based hollow metal−organic framework (HNTM), MoS 2 nanosheets, and a red cell (RBC) membrane. We find that the ultrasound (US)-induced piezoelectric polarization of MoS 2 can improve the charge transfer of HNTM at the heterointerface of HNTM-MoS 2 , increasing the production of reactive oxygen species (ROS). Besides, MoS 2 increases the asymmetric shape of HNTM, leading to the strong US-propelling ability of HNTM−MoS 2 . The produced ROS and strong mechanical force can kill methicillin-resistant Staphylococcus aureus (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 2 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.

sepsis. Nearly 40% Patients suffered from bone infection have the risk of recurrence and chronic infection. [3] Clinical treatments for osteomyelitis involve the long-term and high-dose antibiotics administration, as well as multiple surgical debridement. [4] However, the notable problems of these approaches are obvious. The overuse of antibiotics not only brings severe side effects, but also causes drug-resistant. [5] The removed bone tissue by debridement will weaken the musculoskeletal support and lead to unaesthetic disfigurements. [1] Recent studies showed that controlling antibiotic delivery from nanoparticles or hydrogels could improve the antibacterial efficiency and reduce the dosage of antibiotics, however, superbugs infection still cannot be eliminated efficiently. [6] Given these obstacles, using an antibiotics-free, in situ, and rapid strategy to treat drugresistance bacteria induced osteomyelitis is highly desirable. Photodynamic and photothermal therapies have been intensively reported to treat osteomyelitis, [1,7] but the limited penetration depth of light (visible or near infrared light) cannot fulfill the treatment request of patients with deep bone marrow infection. Alternatively, exogenous stimuli like ultrasound (US) and microwave have strong penetrating ability. [8] Our group recently reported that sonodynamic [9] and microwave therapies [10] can beThe ORCID identification number(s) for the author(s) of this article can be found under

therapy (PDT), the low tissue penetration of light remains a fatal weakness. [1][2][3][4] Relatively, ultrasound (US) with a high tissue-penetration depth has become an important diagnostic tool in clinics. [5] High-intensity focused US can ablate cancer cells in clinical applications through instantaneous heating (65-100°C). [6] Whereas, HIFU cannot eliminate bacteria efficiently under above temperature in a short time without tissue scald. [7] For the SDT, it is desirable to develop a highly efficient sonosensitizer to kill pathogens under mild US (medical imaging grade).At present, the reported sonosensitizer are mainly divided into organic and inorganic categories. [8] Inorganic sonosensitizers, such as TiO 2 NPs, ZnO, Fe 3 O 4 , MnWO x , BaTiO 3, and black phosphorus can generate ROS under US irradiation, but most of them are needed to be decorated with noble metals to improve their SDT efficiency. [9][10][11][12][13][14] In addition, most inorganic nanomaterials cannot be biodegraded, which leads to long-term body retention. [15] Currently, the most widely used organic sonosensitizers in SDT are porphyrins and their derivatives. [16,17] Although most organic sonosensitizers have good biocompatibility, biodegradability, and high ROS production efficiency under US irradiation. [18,19] Sonodynamic therapy (SDT) with non-invasiveness and high tissue-penetrating ability has attracted widespread interest in treating deep-seated tumors or infections. To enhance the treatment efficacy of SDT, the development of high-efficiency and stable sonosensitizers are still needed. Herein, a defective homojunction porphyrin-based metal-organic framework (MOF) with greatly enhanced sonocatalytic ability is easily prepared and used for SDT of osteomyelitis infected by methicillin-resistant Staphylococcus aureus (MRSA). Acetic acid and benzoic acid are chosen as modulators during the hydrothermal synthesis of porphyrin-based MOF. It is found that the crystal structure of MOF shifts from PCN-222 to PCN-224 as the amount of acetic acid increases. Interestingly, the defective PCN (D-PCN) contains a two-phase homojunction structure of PCN-222/PCN-224. The sonocatalytic reactive oxygen species production presents a volcano-type trend with increased acetic acid, among which D-PCN-2 with more content of PCN-224 has the best sonocatalytic antibacterial ability. The reduced band gap introduced a defect, and type-II homojunction structures of D-PCN-2 improve the separation of the ultrasound-triggered electron hole, which significantly enhances the SDT effect. Through a mixed linker approach, this work develops a new defect-induced homojunction MOF with great performance for SDT of MRSA-infected osteomyelitis.

Wound biofilm infection has an inherent resistance to antibiotics, requiring physical debridement combined with chemical reagents or antibiotics in clinical treatment, but it is invasive and may exist as incomplete debridement. So, a new type of noninvasive and efficient treatment is needed to address this problem. Here, the crystal phase engineering of TiO2 is presented to explore the sonocatalytic properties of TiO2 nanoparticles with different phases, and find that the anatase‐brookite TiO2 (AB) has the best antibacterial efficiency of 99.94% against S. aureus under 15 min of ultrasound (US) irradiation. The type II homojunction of AB not only enhances the adsorption and decreases the activation energy of O2, respectively, but also has a great interfacial charge transfer efficiency under US, which can produce more reactive oxygen species than other types of TiO2. The microneedles (MN) penetrate the biofilm in wound tissue and quickly disperse the loaded AB into the biofilm because the ultrasonic cavitation accelerates the dissolution of microneedles, which non‐invasively and efficiently eradicates the deep‐layered biofilm under US. This work explores the relationship between the phase composition of TiO2 and sonocatalytic property for the first time, and provides a new treatment strategy for wound biofilm infection through US‐assisted microneedles therapy.