Regulating inflammation and apoptosis: A smart microgel gene delivery system for repairing degenerative nucleus pulposus

The progression of intervertebral disc degeneration (IDD) is attributed to the gradual exacerbation of cellular apoptosis and impaired extracellular matrix (ECM) synthesis, both of which are induced by progressive inflammation. Therefore, it is crucial to address the inflammatory microenvironment and rectify the excessive apoptosis of nucleus pulposus cells (NPCs) to achieve intervertebral disc (IVD) regeneration. In this study, we devised a smart microgel gene delivery system that incorporates functionalized gene nanoparticles (NPs) for the purpose of IVD regeneration. siGrem1 was loaded into the NPs to enhance their antiapoptotic ability and protective effects. Furthermore, the encapsulation of HADA further endows the NPs (referred to as HSGN) with targeted delivery and anti-inflammatory effects, as well as reactive oxygen species (ROS) scavenging capacities. To create an microenvironment-responsive microgel system, phenylboronic acid-functionalized microspheres (referred to as M.S.) were fabricated and dynamically loaded with the HSGN. This microgel system (MHSGN), which is highly biocompatible, enables the sustained release of siGrem1, effectively modulating inflammation, scavenging ROS, and alleviating apoptosis in NPCs. These multifunctional capabilities promote the restoration of metabolic homeostasis within the nucleus pulposus ECM, ultimately leading to delayed IDD.