Enzymatic bionanocatalysts for combating peri-implant biofilm infections by specific heat-amplified chemodynamic therapy and innate immunomodulation

Zheng Su; Lingtong Kong; Jiawei Mei; Qianming Li; Zhengzheng Qian; Yuanyuan Ma; Yue Chen; Shenghong Ju; Jiaxing Wang; Weitao Jia; Chen Zhu; Wenpei Fan

doi:10.1016/j.drup.2022.100917

Enzymatic bionanocatalysts for combating peri-implant biofilm infections by specific heat-amplified chemodynamic therapy and innate immunomodulation

Drug Resist Updat. 2023 Mar:67:100917. doi: 10.1016/j.drup.2022.100917. Epub 2023 Jan 2.

Authors

Zheng Su¹, Lingtong Kong², Jiawei Mei¹, Qianming Li¹, Zhengzheng Qian³, Yuanyuan Ma⁴, Yue Chen³, Shenghong Ju⁴, Jiaxing Wang⁵, Weitao Jia⁶, Chen Zhu⁷, Wenpei Fan⁸

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
² Department of Orthopedics, The First Affiliated Hospital of Naval Medical University: Changhai Hospital, Shanghai 200433, China.
³ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China.
⁴ Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, 87 DingJiaQiao Road, Nanjing 210009, China.
⁵ Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai 200233, P. R. China. Electronic address: jxwang@shsmu.edu.cn.
⁶ Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai 200233, P. R. China. Electronic address: jiaweitao@shsmu.edu.cn.
⁷ Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China. Electronic address: zhuchena@ustc.edu.cn.
⁸ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China. Electronic address: wenpei.fan@cpu.edu.cn.

PMID: 36608472
DOI: 10.1016/j.drup.2022.100917

Abstract

Bacterial biofilm-associated infection is a life-threatening emergency contributing from drug resistance and immune escape. Herein, a novel non-antibiotic strategy based on the synergy of bionanocatalysts-driven heat-amplified chemodynamic therapy (CDT) and innate immunomodulation is proposed for specific biofilm elimination by the smart design of a biofilm microenvironment (BME)-responsive double-layered metal-organic framework (MOF) bionanocatalysts (MACG) composed of MIL-100 and CuBTC. Once reaching the acidic BME, the acidity-triggered degradation of CuBTC allows the sequential release of glucose oxidase (GOx) and an activable photothermal agent, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). GOx converts glucose into H₂O₂ and gluconic acid, which can further acidify the BME to accelerate the CuBTC degradation and GOx/ABTS release. The in vitro and in vivo results show that horseradish peroxidase (HRP)-mimicking MIL-100 in the presence of self-supplied H₂O₂ can catalyze the oxidation of ABTS into oxABTS to yield a photothermal effect that breaks the biofilm structure via eDNA damage. Simultaneously, the Cu ion released from the degraded CuBTC can deplete glutathione and catalyze the splitting of H₂O₂ into •OH, which can effectively penetrate the heat-induced loose biofilms and kill sessile bacteria (up to 98.64%), such as E. coli and MRSA. Particularly, MACG-stimulated M1-macrophage polarization suppresses the biofilm regeneration by secreting pro-inflammatory cytokines (e.g., IL-6, TNF-α, etc.) and forming a continuous pro-inflammatory microenvironment in peri-implant biofilm infection animals for at least 14 days. Such BME-responsive strategy has the promise to precisely eliminate refractory peri-implant biofilm infections with extremely few adverse effects.

Keywords: Bionanocatalysts; Double-layered metal-organic framework; Heat-amplified chemodynamic therapy; Innate immunomodulation; Peri-implant biofilm infections.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biofilms
Cell Line, Tumor
Escherichia coli
Hot Temperature*
Hydrogen Peroxide / pharmacology
Neoplasms*
Tumor Microenvironment

Substances

2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid
Hydrogen Peroxide