Biodegradable oxygen-evolving metalloantibiotics for spatiotemporal sono-metalloimmunotherapy against orthopaedic biofilm infections

Zheng Su (), Dongdong Xu, Xianli Hu, Wanbo Zhu (), Lingtong Kong, Zhengzheng Qian, Jiawei Mei, Ruixiang Ma, Xifu Shang, Wenpei Fan () and Chen Zhu ()
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Zheng Su: University of Science and Technology of China
Dongdong Xu: The First Affiliated Hospital of Zhengzhou University
Xianli Hu: University of Science and Technology of China
Wanbo Zhu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University
Lingtong Kong: Changhai Hospital of Shanghai
Zhengzheng Qian: China Pharmaceutical University
Jiawei Mei: University of Science and Technology of China
Ruixiang Ma: University of Science and Technology of China
Xifu Shang: University of Science and Technology of China
Wenpei Fan: China Pharmaceutical University
Chen Zhu: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO2-hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H2O2-enriched biofilm microenvironment, MnPM can convert abundant H2O2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair.

Date: 2024
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DOI: 10.1038/s41467-024-52489-x

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