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Although we previously identified the pro\u2010osteogenic role of non\u2010lactylated endosomal trafficking factor 1 (ENTR1), its instability limited therapeutic application. Therefore, we designed DR8 (DENSRLRR), a stable non\u2010lactylated peptide that mimics the functional core of non\u2010lactylated ENTR1, to restore bone homeostasis under high\u2010fat conditions. For effective peptide delivery, we engineered an injectable, reactive oxygen species (ROS)\u2010responsive platform, HPA\/DR8@LPs\u2010E7 (HLP2). In this system, DR8 was loaded into bone\u2010targeting E7 (EPLQLKM) peptide\u2010modified liposomes, which were then encapsulated within a ROS\u2010responsive phenylboronic ester\u2010crosslinked hyaluronic acid\u2010poly(vinyl alcohol) hydrogel. This design facilitated on\u2010demand release within the oxidative bone niche. HLP2 effectively scavenged excess ROS, enhanced cell recruitment, promoted angiogenesis, and potently stimulated osteogenesis. Mechanistically, it modulated paracrine signaling of bone marrow mesenchymal stem cells to restore the receptor activator of nuclear factor \u03baB ligand\/osteoprotegerin balance, thereby suppressing NF\u2010\u03baB signal pathway\u2010mediated osteoclastogenesis. In hyperlipidemic rats with calvarial defects, HLP2 significantly accelerated bone regeneration. This study has established a paradigm\u2010shifting strategy that synergizes a multifunctional metabolic peptide with an adaptive biomaterial platform for the treatment of metabolic bone disorders.<\/jats:p>","DOI":"10.1002\/adhm.202505684","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T09:09:38Z","timestamp":1771664978000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["An Injectable Liposome\u2013Hydrogel Composite for Targeted Delivery of a Non\u2010Lactylated Peptide to Rebalance Bone Metabolism in Hyperlipidemia"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1061-1576","authenticated-orcid":false,"given":"Tiantian","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Prosthodontics, Cheeloo College of Medicine, School and Hospital of Stomatology, Shandong University, Shandong Key Laboratory of Oral Tissue 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