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Osteomyelitis caused by methicillin‐resistant Staphylococcus aureus (MRSA) biofilm infection is difficult to eradicate and can even be life‐threatening. Given that the infection is persistent and deep‐seated in the bone tissue, controlled and efficient treatment of osteomyelitis remains challenging. Herein, an activatable nanostructure (Au/TNT@PG) is presented for synergistic sonodynamic‐catalytic therapy of MRSA‐infected osteomyelitis. The Au/TNT@PG backbone is obtained by conjugating a guanidinium‐rich polymer (PG), a component that penetrates the biofilm matrix, onto ultrasound (US)‐absorbing gold‐doped titanate nanotubes (Au/TNTs). Under deep‐penetrating US irradiation, the nanocomposite generates 1O2 for sonodynamic therapy and catalyzes the decomposition of endogenous H2O2 into toxic •OH in the acidic infection microenvironment for catalytic therapy, leading to bacterial cell death. Its robust antibacterial effectiveness is attributable to its bacteria‐capturing ability, the biofilm penetrability of positively charged guanidinium, and the subsequent synergistic effect of sonodynamic‐catalytic action of Au/TNT. Such a remotely controlled approach potentiates the polarization of macrophages to M2‐type while suppressing the M1‐type, leading to topical inflammation resolution and enhanced osteoblast proliferation and differentiation to inhibit bone loss. Therefore, this study provides a generic nanotherapeutic approach for efficient sonodynamic‐catalytic therapy with respect to osteomyelitis.

Chronic infections caused by Pseudomonas aeruginosa pose severe threats to human health. Traditional antibiotic therapy has lost its total supremacy in this battle. Here, nanoplatforms activated by the clinical microenvironment are developed to treat P. aeruginosa infection on the basis of dynamic borate ester bonds. In this design, the nanoplatforms expose targeted groups for bacterial capture after activation by an acidic infection microenvironment, resulting in directional transport delivery of the payload to bacteria. Subsequently, the production of hyperpyrexia and reactive oxygen species enhances antibacterial efficacy without systemic toxicity. Such a formulation with a diameter less than 200 nm can eliminate biofilm up to 75%, downregulate the level of cytokines, and finally promote lung repair. Collectively, the biomimetic design with phototherapy killing capability has the potential to be an alternative strategy against chronic infections caused by P. aeruginosa.

Chronic osteomyelitis is an inflammatory skeletal disease caused by a bacterial infection that affects the periosteum, bone, and bone marrow. Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent. The bacterial biofilm formed on the necrotic bone is a considerable challenge to treating MRSA-infected osteomyelitis. Here, we developed an all-in-one cationic thermosensitive nanotherapeutic (TLCA) for treating MRSA-infected osteomyelitis. The prepared TLCA particles were positively charged and <230 nm in size, which allowed them to diffuse effectively into the biofilm. The positive charges of the nanotherapeutic accurately targeted the biofilm, and it subsequently regulated the drug release under near-infrared (NIR) light irradiation, thereby efficiently exerting the synergistic effect of NIR light-driven photothermal sterilization and chemotherapy. More than 80% of the antibiotics were abruptly released at 50 °C, which dispersed the biofilm by up to 90%. When applied to MRSA-infected osteomyelitis, with a localized temperature of 50 °C induced by 808 nm laser irradiation, it not only eliminated the bacteria and controlled infection but also inhibited the bone tissue inflammatory response, significantly reducing TNF-α, IL-1β, and IL-6 levels. In conclusion, we constructed an all-in-one antimicrobial treatment modality that provides a new and effective strategy for the topical treatment of chronic osteomyelitis.

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