Orchestrated Engineered Polyphenol‐Peptide Condensates Coupled With β‐GP Reverses Diabetic Osteoporosis by Remodeling Mitophagy

ABSTRACT Diabetic osteoporosis (DOP) is a chronic complication of diabetes mellitus characterized by reduced bone mass, disrupted microarchitecture, and an elevated fracture risk. Persistent oxidative stress and inflammation further inhibit osteogenesis and angiogenesis, accelerating bone degeneration. In this study, we used a peptide‐polyphenol conjugation strategy to develop a multifunctional colloidal nanoplatform (β‐GP@EGCG‐E7). The bone‐targeting peptide E7 was covalently conjugated with epigallocatechin‐3‐ gallate (EGCG) and subsequently loaded with β‐glycerophosphate (β‐GP). Sequentially, this nanoplatform integrates bone‐targeted delivery, improving mitochondrial quality by anti‐inflammation and antioxidation, as well as osteogenesis and angiogenesis within a single system. In detail, in a high glucose microenvironment, the nanoplatform selectively accumulates in bone lesions, scavenges excess intracellular reactive oxygen species (ROS) triggered by high glucose, clears damaged mitochondria by activating PINK1‐Parkin mediated mitophagy, and exerts anti‐inflammatory effects to rebalance the microenvironment of bone regeneration. Concurrently, sustained phosphate release supports mineralization, promotes osteogenic differentiation, enhances angiogenesis, and improves local microcirculation. In diabetic osteoporotic models, β‐GP@EGCG‐E7 significantly reduced oxidative stress, restored mitochondrial homeostasis, and promoted bone and vascular regeneration. This study provides a promising therapeutic strategy for DOP and highlights the potential of peptide‐polyphenol hybrid nanomaterials for regenerative applications.