Peptide-modified mesoporous silica nanoparticles for the coordinated regulation of macrophage polarization and pyroptosis in the treatment of implant-related infections
Zhi Li, Yuhang Wang, Xingshi Yuan, Ming‐you Xu, Xiaofang Wang, Chang Liu, Zhu Chen, Wei Pei, Jiaxiang Bai, Xifu Shang
Abstract
Implant-related infections (IRIs) present a significant challenge in clinical treatment because of the formation of biofilms. The complex architecture of biofilms not only impedes antibiotic penetration, fostering the evolution of multidrug resistance in bacteria under minimal selective pressure but also suppresses the antimicrobial activity of macrophages and induces their pyroptosis in large quantities. This excessive pyroptosis impairs the collective immune function of macrophages, enabling pathogens to evade immune system clearance and rendering infection difficult to eradicate. Existing treatment strategies often necessitate extensive surgical debridement, which not only causes significant harm to patients' physiological health and quality of life but also results in limited therapeutic outcomes. To address these challenges, this study developed a mesoporous silica nanoparticle system (MRL) modified with the RGD (Arginine-Glycine-Aspartic acid) tripeptide and loaded with the antimicrobial peptide LL-37. The LL-37 released from MRL can not only directly disrupt bacterial cell membranes, preventing bacteria from developing resistance through conventional mutation mechanisms, but also enhance antimicrobial activity by modulating macrophage polarization toward the M1 phenotype. However, LL-37 may induce and exacerbate macrophage pyroptosis within biofilms. Therefore, we modified the nanoparticles with RGD to increase macrophage viability and reduce their number of deaths, thereby alleviating the immunosuppression caused by excessive macrophage pyroptosis. In vitro and in vivo experiments demonstrated that MRL, while preserving the antimicrobial activity and immunomodulatory function of LL-37, significantly reduced macrophage pyroptosis and protected the collective immune activity of macrophages. Thus, the fine-tuned regulation of immune response was achieved, providing new insights and strategies for the treatment of IRIs.