Nanoadjuvant-triggered STING activation evokes systemic immunotherapy for repetitive implant-related infections

Abstract

Repetitive implant-related infections (IRIs) are devastating complications in orthopedic surgery, threatening implant survival and even the life of the host. Biofilms conceal bacterial-associated antigens (BAAs) and result in a ''cold tumor''-like immune silent microenvironment, allowing the persistence of IRIs. To address this challenge, an iron-based covalent organic framed nanoadjuvant doped with curcumin and platinum (CFCP) was designed in the present study to achieve efficient treatment of IRIs by inducing a systemic immune response. Specifically, enhanced sonodynamic therapy (SDT) from CFCP combined with iron ion metabolic interference increased the release of bacterial-associated double-stranded DNA (dsDNA). Immunogenic dsDNA promoted dendritic cell (DC) maturation through activation of the stimulator of interferon gene (STING) and amplified the immune stimulation of neutrophils via interferon-β (IFN-β). At the same time, enhanced BAA presentation aroused humoral immunity in B and T cells, creating long-term resistance to repetitive infections. Encouragingly, CFCP served as neoadjuvant immunotherapy for sustained antibacterial protection on implants and was expected to guide clinical IRI treatment and relapse prevention.

Keywords

• Implant-related infections
• Systemic immunotherapy
• cGAS-STING pathway
• Interferon
• Neutrophil activation