A Metal–Phenolic Network-Coated Coacervate System Mediates Mitochondrial Modulation and Bone Homeostasis Restoration for Postmenopausal Osteoporosis Therapy

Postmenopausal osteoporosis (PMOP) manifests as a systemic skeletal disorder arising from disrupted bone metabolic equilibrium, characterized by a marked reduction in bone mineral density and compromised microarchitectural integrity, ultimately leading to increased bone fragility and greater fracture susceptibility. Current delivery therapeutic strategies frequently fail to address mitochondrial dysfunction arising from estrogen depletion and senescence-associated processes. We developed a multifunctional coacervate system, in which peptide coacervates were used to encapsulate estradiol (E2) and subsequently coated by a metal-phenolic network (MPN), capable of concurrently modulating mitochondrial function and reconstructing bone homeostasis. The MPN-coated coacervates demonstrate microenvironment-responsive degradation within osteoporotic bone tissue. In ovariectomized aged mouse models, intravenous injection of these coacervates significantly increased bone volume in both the femur and vertebrae while mitigating side effects on the uterus. This unique therapeutic paradigm establishes a bidirectional regulatory mechanism that provides a promising strategy for comprehensive osteoporosis management.