Microenvironment-targeted strontium delivery system reshapes redox homeostasis to halt degenerative cascades in intervertebral discs.

Intervertebral disc degeneration (IVDD) is mainly caused by oxidative stress, leading to cellular aging and breakdown of the extracellular matrix (ECM). Current treatments do not specifically or consistently modify the degenerative environment. To solve this, we developed pH-responsive, strontium-functionalized double-network microspheres (RGD-SA/HA-His-Sr, rSA-HHS) using microfluidic technology. This system combines three key components: RGD-modified alginate for mechanical support and better cell-matrix interaction; histidine-grafted hyaluronic acid for environment-triggered degradation at low pH and reactive oxygen species scavenging; and strontium ions bound through multidentate coordination to control antioxidant responses. The design allows for the controlled release of bioactive ions in acidic disc areas. In vitro tests show sustained ion release over 28 days, reducing cellular aging and inflammation in nucleus pulposus cells while increasing collagen type II and aggrecan production. In vivo rat models of IVDD demonstrate improved disc height and ECM regeneration. The rSA-HHS platform offers a multitarget approach by simultaneously addressing oxidative stress, inflammation, and biomechanical issues. This research highlights important antioxidant mechanisms and presents a new, precise method for disc regeneration that goes beyond single-target biomaterials.