Modulating Macrophage–Nucleus Pulposus Cell Crosstalk via Sequential Drug Delivery Attenuates Disc Degeneration

Abstract Intervertebral disc degeneration (IDD) is characterized by an inflammatory environment and dysregulation of the extracellular matrix metabolism (ECM). Improving nucleus pulposus cells (NPCs) condition first requires a supportive surrounding environment. However, how to provide an excellent microenvironment before regulating the function of the NPCs is not yet a complete strategy. In this study, a sequential drug delivery system is comprised of chitosan hydrogel (G‐CS) loaded with Angiotensin (1‐7) and mesoporous silica nanospheres (MSN) coating with α‐mangostin to achieve synergistic effects of anti‐inflammatory and regulation of metabolic disorders of the ECM in NPCs. The system first explosively releases outer G‐CSloaded Angiotensin (1‐7) by exploiting the different solubility characteristics of the two drugs, which improves the inflammatory environment by inhibiting the integrated stress response and regulating the macrophage phenotype. During the second stage, the inner layer of the MSN controlled‐release loaded α‐mangostin to regulate ECM metabolism and synthesis, slowing cell aging and apoptosis. Furthermore, α‐mangostin promotes mitophagy in NPCs by inhibiting the PI3K/AKT/mTOR pathway and activating the Pink1/Parkin pathway, promoting the clearance of damaged mitochondria. The proposed drug delivery system represents an innovative and promising strategy for treating IDD.