Translational Macrophage Mechano‐Immunotherapy for Next‐Generation Implantable Biomaterials

Decades of work have demonstrated that macrophages actively sense and respond to stiffness, strain and topography, making mechanical cues central determinants of inflammation, fibrosis and eventual maladaptive tissue remodelling of implanted biomaterials. Traditional strategies have focused on engineering implants to mimic native tissue mechanics. However, these material‐based approaches alone often fail to fully control immune and fibrotic outcomes. Recent advances in pharmacological modulation of mechanosensitive targets highlight the therapeutic potential of ‘mechano‐immunotherapy’ in the context of macrophage activation during foreign body responses. Preclinical implant studies highlight therapeutic opportunities and challenges, while clinical experience with selected agents derives from non‐implant indications and does not establish efficacy against implant‐associated foreign body responses. Advances in biomaterial platforms offer conceptual routes to spatially and temporally control mechanotransduction‐modulating drugs at the implant–tissue interface, without fundamentally altering the implant itself. Translating these approaches will require standardised mechanosensing assays and early regulatory engagement to navigate combination product classification and evidentiary requirements. This review synthesises current knowledge of mechanosensitive pathways, drug development, clinical progress in non‐implant indications and biomaterial‐based delivery strategies, providing a roadmap for localised macrophage mechano‐immunotherapy to improve implant integration and long‐term device performance.