Ultrasound-Responsive Microneedles Eradicate Deep-Layered Wound Biofilm Based on TiO2 Crystal Phase Engineering.

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.

Ultrasonic Interfacial Engineering of MoS2 -Modified Zn Single-Atom Catalysts for Efficient Osteomyelitis Sonodynamic Ion Therapy.

Osteomyelitis is considered as the most serious bone infection, which can lead to the bone destruction or fatal sepsis. Clinical treatments through frequent antibiotics administration and surgical debridement bring inevitable side effects including drug-resistance and disfigurements. It is urgent to develop an antibiotics-free and rapid strategy to treat osteomyelitis. Herein, a bifunctional sonosensitizer that consists of porphyrin-like Zn single-atom catalysts (g-ZnN4 ) and MoS2 quantum dots is developed, which exhibits excellent sonodynamic antibacterial efficiency and osteogenic ability. It is found that the construction of heterogeneous interfaces of g-ZnN4 -MoS2 fully activates the adsorbed O2 due to the increased interface charge transfer, enhanced spin-flip, and reduced activation energy of O2 . The generated 1 O2 can kill methicillin-resistant Staphylococcus aureus (MRSA) with an antibacterial efficiency of 99.58% under 20 min of ultrasound (US) irradiation. The Zn single atoms immobilized in g-ZnN4 can be released steadily in the form of Zn2+ for 28 days within safe concentration, realizing the great osteoinductive ability of such a sonosensitizer. For the treatment of MRSA-infected osteomyelitis, the inflammation and bone loss can be significantly suppressed through sonodynamic ion therapy. This work provides another strategy for developing high efficiency sonosensitizer through ultrasound interfacial engineering.

Defective Homojunction Porphyrin-Based Metal-Organic Frameworks for Highly Efficient Sonodynamic Therapy.

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.

Ultrasound-Induced Abiotic and Biotic Interfacial Electron Transfer for Efficient Treatment of Bacterial Infection.

Electron transfer plays an important role in various catalytic reactions and physiological activities, whose altered processes may change catalytic efficiency and interfere in physiological metabolic processes. In this study, we design an ultrasound (US)-activated piezoelectric responsive heterojunction (PCN-222-BTO, PCN: porous coordination network), which can change the electron transfer path at the abiotic and abiotic-biotic interfaces under US, thus achieving a rapid (15 min) and efficient bactericidal effect of 99.96%. US-induced polarization of BTO generates a built-in electric field, which promotes the electron transfer excited from PCN-222 to BTO at the PCN-222-BTO interface, thereby increasing the level of reactive oxygen species (ROS) production. Especially, we find that the biological electron transfer from the bacterial membrane to BTO is also activated at the MRSA-BTO interface. This antibacterial mode results in the down-regulated ribosomal, DNA and ATP synthesis related genes in MRSA, while the cell membrane and ion transport related genes are up-regulated due to the synergistic damage effect of ROS and disturbance of the bacterial electron transport chain. This US responsive dual-interface system shows an excellent therapeutic effect for the treatment of the MRSA-infected osteomyelitis model, which is superior to clinical vancomycin therapy.

Piezo-Augmented Sonosensitizer with Strong Ultrasound-Propelling Ability for Efficient Treatment of Osteomyelitis.

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), MoS2 nanosheets, and a red cell (RBC) membrane. We find that the ultrasound (US)-induced piezoelectric polarization of MoS2 can improve the charge transfer of HNTM at the heterointerface of HNTM-MoS2, increasing the production of reactive oxygen species (ROS). Besides, MoS2 increases the asymmetric shape of HNTM, leading to the strong US-propelling ability of HNTM-MoS2. 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-MoS2 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.