pH- and redox-sensitive selenium-incorporated mesoporous silica nanoparticles for osteosarcoma-targeted treatment

• A dual-stimuli-responsive mesoporous silica nanoparticle system for osteosarcoma-targeted therapy was developed. • Integrated selenium nanoparticles and doxorubicin to enable controlled drug release under tumor-specific conditions. • Selectively killed osteosarcoma cells while sparing normal bone cells by modulating oxidative stress. • Highlights the potential of nanocarriers and oxidative stress regulation in targeted cancer therapies. Elevating oxidative stress presents a promising osteosarcoma (OS) treatment strategy, as it can selectively induce cell death in OS cells. Selenium nanoparticles (SeNPs) and doxorubicin (Dox) have shown promise in this regard by effectively upregulating oxidative stress. However, limitations, such as nanoparticle aggregation, inefficient intracellular uptake, and high-dose toxicity, hinder their therapeutic potential. Stimuli-responsive release can address these issues by enhancing effectiveness and minimizing side effects. In this paper, stimuli-responsive release of SeNPs/Dox for enhanced OS therapy is investigated. The introduction of a mesoporous silica coating (MS) onto SeNPs (SeMS) was used to prevent aggregation and allow for Dox co-encapsulation. The MS surface was further functionalized with hyaluronic acid (HA) using disulfide bonds (to create SeMS Dox -SS-HA), to function as a gatekeeper and to enable pH- and redox-responsive release. Our results demonstrate low pH and elevated GSH levels can activate SeMS Dox -SS-HA, resulting in rapid Dox/Se release within OS cells. Moreover, SeMS Dox -SS-HA show significantly heightened OS inhibition, attributed to the differential reactive oxygen species (ROS) production and glutathione (GSH) depletion within OS cells, while hMSCs remained unaffected. These findings suggest that this pH/GSH-responsive MS delivery system encapsulating SeNPs and Dox represents a promising nanoplatform for OS-selective therapy through redox modulation.