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. In vivo 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.