HydroWrap for T2DM-Related Fractures: A smart H2S-delivery controller modulating Macrophage senescence

Impaired fracture healing in type 2 diabetes mellitus (T2DM) poses a significant clinical challenge, primarily due to a compromised bone microenvironment driven by senescent macrophages and their amplifying effects. Reduced hydrogen sulfide (H₂S) levels are a critical contributor to this pathology. To address this, we developed HydroWrap, an advanced H₂S-delivery controller designed to modulate distinct stages of macrophage senescence. Under near-infrared (NIR) irradiation, HydroWrap underwent an increase in temperature, causing the hydrogel network to contract and accelerate H₂S generation. This rapid delivery restores H₂S levels, alleviating mitochondrial dysfunction and suppressing senescence-associated secretory phenotypes (SASP), thereby interrupting the senescence cascade. In T2DM's hyperglycemic bone microenvironment, HydroWrap provides sustained, glucose-responsive H₂S release, promoting mitophagy and preventing macrophage senescence progression. This dual mechanism addresses both acute and chronic dysfunctions associated with senescence. <i>In vivo</i> studies demonstrated that HydroWrap significantly improved fracture healing by reducing recovery time and enhancing bone quality. These findings underscore the therapeutic potential of modulating macrophage senescence in T2DM using a biocompatible drug delivery system. HydroWrap offers a promising strategy for improving fracture outcomes in diabetic patients and may hold broader applications in senescence-related diseases.