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Adv."],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:p>Intervertebral disc degeneration (IVDD), driven by progenitor cell loss and oxidative stress, remains a major clinical challenge with limited effective regenerative therapies. Here, we present a \u201cProgenitor Cell Ark,\u201d a triple-layered hydrogel microsphere system designed for synergistic cell delivery and microenvironment remediation. The Ark comprises an outer nucleus pulposus progenitor cell (NPPC) layer for cell replenishment, a middle GelMA\/HAMA scaffold for support, and an inner SS31-modified ultrasmall Prussian blue nanozyme (SS31-UPN) layer that specifically targets mitochondria to scavenge ROS and promote mitophagy. In vitro, SS31-UPN effectively protected NPPCs from oxidative damage, restored mitochondrial function, and enhanced mitophagy. Critically, in severe IVDD rat models, the Progenitor Cell Ark significantly improved intervertebral disc structure, promoted neo-tissue formation, and restored biomechanical function, outperforming cell or bioscaffold therapy alone. Mechanistically, we demonstrate that SS31-UPN\u2019s mitochondrial targeting enhances mitophagy, drives ECM and energy metabolic remodeling, and preserves NPPC stemness, thereby creating a proregenerative milieu. This integrated \u201ccell-in-a-box\u201d strategy offers a robust platform for reversing IVDD and holds notable translational potential for regenerative medicine.<\/jats:p>","DOI":"10.1126\/sciadv.aeh5001","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:59:24Z","timestamp":1792000764000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["A \u201cProgenitor Cell Ark\u201d hydrogel system for intervertebral disc regeneration via mitochondrial targeting and mitophagy enhancement"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5432-5511","authenticated-orcid":true,"given":"Yilin","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Soochow University, Orthopedic Institute, Soochow University, Suzhou, Jiangsu 215006, P. R. 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