Cascade targeting selenium nanoparticles-loaded hydrogel microspheres for multifaceted antioxidant defense in osteoarthritis

Abstract

Selenium (Se) deficiency is a critical factor contributing to the imbalance of redox homeostasis in chondrocytes and the progression of osteoarthritis (OA). However, traditional selenium supplements face challenges such as a narrow therapeutic window and lack of targeting. To address this, we designed hyaluronic acid (HA)-modified selenium nanoparticles (HA-SeNPs) and developed a cascade-targeted delivery system (HA-SeNPs@AHAMA-HMs) based on a nano-micron combined strategy. The system involves loading HA-SeNPs into aldehyde-functionalized hydrogel microspheres prepared via microfluidic technology. Through Schiff base reactions between the aldehyde groups of the microspheres and amino groups of the cartilage, the system selectively adheres to the surface of damaged cartilage, achieving micron-scale targeting while continuously releasing HA-SeNPs. Then, HA-SeNPs achieve nanoscale targeting by binding to CD44, which is highly expressed on OA chondrocyte membranes, via their HA surface. Once taken up by the cells, HA-SeNPs exert their effects by directly scavenging ROS and promoting selenoprotein synthesis through the generation of selenite, forming a multifaceted antioxidant defense system. This effectively alleviates oxidative stress and optimizes mitochondrial function. In vivo and in vitro results demonstrated that this system significantly improved the oxidative phosphorylation pathway associated with mitochondrial function, which markedly reduced joint space narrowing and cartilage matrix degradation, and delayed the progression of OA. In summary, this study suggests that the cascade-targeting hydrogel microspheres designed and constructed based on a nano-micron combined strategy represent a promising prospective approach for precise Se supplementation and OA treatment.