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Herein, we developed an ultrasmall pH\u2010responsive nanoplatform (FeAst) through the self\u2010assembly of Fe\n                    <jats:sup>3+<\/jats:sup>\n                    and the natural flavonoid Astragalin (Ast) for injury\u2010responsive renal delivery and metabolic intervention. The Fe\n                    <jats:sup>3+<\/jats:sup>\n                    \u2013phenolic coordination network endows FeAst with excellent biocompatibility, intrinsic reactive oxygen species (ROS)\u2010scavenging capacity, and mitochondria\u2010targeting capability. Importantly, FeAst preferentially accumulated in injured kidneys, enabling targeted renal delivery. Moreover, the mildly acidic microenvironment associated with AKI triggered partial dissociation of the coordination network, enabling localized Ast release and sustained therapeutic activity. Across multiple experimental models of kidney injury, FeAst markedly improved renal function, alleviated tubular injury, suppressed inflammatory responses, and restored redox homeostasis. Mechanistically, FeAst preserved mitochondrial integrity, re\u2010established glutathione\u2010dependent antioxidant defense, suppressed ferroptosis\u2010related processes by reducing lipid peroxidation and restoring ferroptosis defense systems, and reprogrammed TCA cycle\u2010associated energy metabolism. Moreover, FeAst activated PPAR signaling and suppressed p38 MAPK\/NF\u2010\u03baB\u2010mediated inflammatory responses, thereby enhancing cellular bioenergetics and resistance to oxidative stress. Collectively, this injury\u2010responsive nanoplatform integrates selective renal accumulation, controlled drug release, and metabolic reprogramming to provide a promising strategy for precision kidney injury therapy.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71849","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:31:12Z","timestamp":1792038672000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Mitochondria\u2010Targeted and pH\u2010Responsive Fe\n                    <sup>3+<\/sup>\n                    \u2013Astragalin Nanoplatform Reprograms Metabolism to Protect Against Acute Kidney Injury"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9240-7675","authenticated-orcid":false,"given":"Shichao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Xie","sequence":"additional","affiliation":[{"name":"Intensive Care Unit Institute of Infectious Diseases The Second Hospital of Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjiong","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shushuai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenglong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengfei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin China"},{"name":"Kaifeng Central Hospital  Kaifeng Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qidan","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Urology Tianjin Institute of Urology The Second Hospital of Tianjin Medical University  Tianjin 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