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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\u2010CS) loaded with Angiotensin (1\u20107) and mesoporous silica nanospheres (MSN) coating with \u03b1\u2010mangostin to achieve synergistic effects of anti\u2010inflammatory and regulation of metabolic disorders of the ECM in NPCs. The system first explosively releases outer G\u2010CSloaded Angiotensin (1\u20107) 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\u2010release loaded \u03b1\u2010mangostin to regulate ECM metabolism and synthesis, slowing cell aging and apoptosis. Furthermore, \u03b1\u2010mangostin 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.<\/jats:p>","DOI":"10.1002\/advs.202507178","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T22:50:26Z","timestamp":1751323826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Modulating Macrophage\u2013Nucleus Pulposus Cell Crosstalk via Sequential Drug Delivery Attenuates Disc Degeneration"],"prefix":"10.1002","volume":"12","author":[{"given":"Xiangzhen","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine Shandong University  Jinan Shandong 250012 P. R. China"},{"name":"Qilu Hospital of Shandong University  Jinan Shandong 250012 P. R. 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