Precise Clearance of Intracellular MRSA via Internally and Externally Mediated Bioorthogonal Activation of Micro/Nano Hydrogel Microspheres
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Updated: Jul 14, 2026
Photodegradable Hydrogel Interfaces for Bacteria Screening, Selection, and Isolation
Published on: November 4, 2021
Jianye Yang1, Li Chen1, Zhengwei Cai2
1Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, P. R. China.
Abstract:
Traditional high-dose antibiotic treatments of intracellular methicillin-resistant staphylococcus aureus (MRSA) are highly inefficient and associated with a high rate of infection relapse. As an effective antibacterial technology, sonodynamic therapy (SDT) may be able to break the dilemma. However, indiscriminate reactive oxygen species (ROS) release leads to potential side effects. This study incorporates Staphylococcal Protein A antibody-modified Cu2+/tetracarboxyphenylporphyrin nanoparticles (Cu(II)NS-SPA) into hydrogel microspheres (HAMA@Cu(II)NS-SPA) to achieve precise eradication of intracellular bacteria. This eradication is under bioorthogonal activation mediated by bacillithiol (BSH) (internally) and ultrasound (US) (externally). To specify, the US responsiveness of Cu(II)NS-SPA is restored when it is reduced to Cu(I)NS-SPA by the BSH secreted characteristically by intracellular MRSA, thus forming a bioorthogonal activation with the external US, which confines ROS production within the infected MΦ. Under external US activation at 2 W cm-2, over 95% of intracellular MRSA can be cleared. In vivo, a single injection of HAMA@Cu(II)NS-SPA achieves up to two weeks of antibacterial sonodynamic therapy, reducing pro-inflammatory factor expression by 90%, and peri-implant bone trabeculae numbers exceed the control group by five times. In summary, these micro/nano hydrogel microspheres mediated by internal and external bioorthogonal activation can precisely eliminate intracellular MRSA, effectively treating multi-drug resistant intracellular bacterial infections.
Insights
This study introduces novel hydrogel microspheres for precisely targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA). The innovative approach uses bioorthogonal activation to effectively eliminate bacteria with reduced side effects.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Infectious Diseases
Background:
- Traditional antibiotic treatments for intracellular MRSA are inefficient and lead to relapse.
- Sonodynamic therapy (SDT) shows promise but suffers from indiscriminate reactive oxygen species (ROS) release and side effects.
- A targeted approach is needed to overcome the limitations of current MRSA therapies.
Purpose of the Study:
- To develop a precise and effective strategy for eradicating intracellular MRSA.
- To utilize bioorthogonal activation for localized ROS production and minimize side effects.
- To evaluate the therapeutic efficacy of the developed system in vitro and in vivo.
Main Methods:
- Fabrication of Staphylococcal Protein A antibody-modified Cu2+/tetracarboxyphenylporphyrin nanoparticles (Cu(II)NS-SPA) encapsulated in hydrogel microspheres (HAMA@Cu(II)NS-SPA).
- Bioorthogonal activation triggered by bacillithiol (BSH) secreted by intracellular MRSA and external ultrasound (US) stimulation.
- Assessment of intracellular MRSA clearance, ROS confinement, pro-inflammatory factor reduction, and bone regeneration in vitro and in vivo models.
Main Results:
- Over 95% of intracellular MRSA was cleared under external US activation (2 W cm-2).
- In vivo studies showed sustained antibacterial activity for two weeks, a 90% reduction in pro-inflammatory factors, and a five-fold increase in bone trabeculae.
- The system demonstrated precise eradication of intracellular bacteria with confined ROS production.
Conclusions:
- The developed micro/nano hydrogel microspheres offer a precise and effective treatment for intracellular MRSA infections.
- Internal and external bioorthogonal activation enables targeted bacterial elimination and reduces potential side effects.
- This approach holds significant potential for treating multi-drug resistant intracellular bacterial infections.
