Beyond Drug Delivery: Metal–Organic Framework-Derived Nanosystems for Bone Regeneration under Complicated Pathological Microenvironments

ConspectusThe development of tactics to effectively manage various bone illnesses, including bone abnormalities, bone infections, fractures, osteoarthritis, osteoporosis, and malignancies, has become a significant public health concern for achieving optimal bone repair outcomes. Conventionally, bisphosphonates and monoclonal antibody medications have shown partial clinical efficacy in bone regeneration. However, issues such as medication resistance, life-threatening off-target side effects, and poor bioavailability continue to affect the majority of patients. Additionally, surgical interventions like subchondral bone microfracture, lavage, debridement, and shaving are primarily effective for minor bone defects. For severe bone defects, the gold standard treatment involves implanting autologous or allogeneic bone grafts. Nevertheless, these grafts come with challenges, such as donor site complications, immune rejection, infections, and limited tissue availability.Recent years have seen the rapid development of new therapeutic strategies that have significantly revolutionized the course of bone regeneration. Metal–organic frameworks (MOFs) are a class of porous materials consisting of metal–metal clusters and organic ligands. Over the past few decades, MOF-based nanosystems have been extensively applied as versatile drug delivery systems for transporting small molecules, genes, peptides, and proteins owing to their distinct coordination network, porous structure, feasible surface modification, and adjustable porosity. Notably, the versatile nanostructure and composition of MOFs allow customization of their metal cations and defect locations within the porous structure to meet the complex requirements of the bone tissue microenvironment. Additionally, MOF-based nanosystems can be harnessed with corresponding functional components, thus achieving selective depletion of overproduced danger signals, blockage of the receptor for the pleiotropic inflammatory molecules, and delivery of therapeutic agents to target sites, hence boosting its effectiveness in bone regeneration.In this Account, we systematically highlight the fundamental aspects of MOF-based nanosystem design with a specific focus on critical factors such as chemical composition, shape, size, and surface chemistry. Subsequently, we review recent achievements of MOF-based nanosystems beyond drug delivery, specifically their utilization in bone regeneration under complex pathological conditions. Given the complicated characteristics of bone regeneration that require a multifaceted and dynamic approach, these strategies exemplify the innovative efforts needed to overcome the challenges posed by this complex disease. With significant strides in understanding the molecular mechanisms underlying bone defects, coupled with advances in bioengineering techniques, more efficient MOF-based nanosystems will be designed and applied in bone regeneration in the future. This progress will bridge the gap between basic research and clinical applications, ultimately enhancing the therapeutic effectiveness of treatments for bone regeneration in complicated pathological microenvironments.