An Injectable Liposome–Hydrogel Composite for Targeted Delivery of a Non‐Lactylated Peptide to Rebalance Bone Metabolism in Hyperlipidemia

The pathological bone microenvironment in hyperlipidemia severely impedes regeneration, which is a challenge that is poorly addressed by current therapies. Although we previously identified the pro-osteogenic role of non-lactylated endosomal trafficking factor 1 (ENTR1), its instability limited therapeutic application. Therefore, we designed DR8 (DENSRLRR), a stable non-lactylated peptide that mimics the functional core of non-lactylated ENTR1, to restore bone homeostasis under high-fat conditions. For effective peptide delivery, we engineered an injectable, reactive oxygen species (ROS)-responsive platform, HPA/DR8@LPs-E7 (HLP2). In this system, DR8 was loaded into bone-targeting E7 (EPLQLKM) peptide-modified liposomes, which were then encapsulated within a ROS-responsive phenylboronic ester-crosslinked hyaluronic acid-poly(vinyl alcohol) hydrogel. This design facilitated on-demand 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 κB ligand/osteoprotegerin balance, thereby suppressing NF-κB signal pathway-mediated osteoclastogenesis. In hyperlipidemic rats with calvarial defects, HLP2 significantly accelerated bone regeneration. This study has established a paradigm-shifting strategy that synergizes a multifunctional metabolic peptide with an adaptive biomaterial platform for the treatment of metabolic bone disorders.