Natural Smart Hydrogels for Osteoporosis Therapy: Dynamic Sensing, Targeted Delivery, and Bone Remodeling

Osteoporosis is a prevalent bone metabolic disorder globally, constituting a significant public health concern. Traditional therapeutic approaches, such as calcium supplementation and anti-resorptive medications, frequently exhibit limited absorption, adverse side effects, and inadequate regulation of bone remodeling processes. In recent developments, natural smart hydrogels have emerged as promising next-generation therapeutic options for osteoporosis. These materials possess the ability to emulate the bone microenvironment, detect pathological alterations, and deliver therapeutic agents with precision. This review provides a comprehensive overview of the recent advancements in the application of natural smart hydrogels for osteoporosis treatment, with an emphasis on their dynamic sensing mechanisms, targeted delivery systems, and contributions to bone remodeling. Furthermore, we address critical challenges, including the synchronization of degradation with regeneration, optimization of multi-factor release, and enhancement of clinical translation. Finally, we propose prospective directions centered on programmable design and intelligent feedback regulation to facilitate personalized and adaptive treatment strategies. This review aims to offer novel insights into the development of intelligent biomaterials for precision bone regeneration. Natural responsive hydrogels are designed to detect the pathological bone microenvironment, which is characterized by acidic pH, excessive reactive oxygen species (ROS), chronic inflammation, and impaired structural reconstruction. These hydrogels initiate structural adaptation dependent on the microenvironment and facilitate the on-demand release of therapeutic agents. When implanted into osteoporotic lesions, these polysaccharide-based hydrogels orchestrate the targeted delivery of calcium/minerals, pharmaceuticals, bioactive molecules, and gene/protein therapeutics to restore the balance between osteogenesis and osteoclastogenesis, while simultaneously regulating angiogenesis and immune homeostasis. By integrating the modulation of osteogenic signaling, suppression of osteoclast activity, vascular regeneration, and mechanical coupling, this advanced hydrogel system enhances multidimensional bone remodeling. This underscores its potential for personalized and clinically translatable osteoporosis therapy. • Smart hydrogels enable dynamic sensing of osteoporosis microenvironment; • Polysaccharide matrices achieve multi-factorial and targeted bone delivery; • Responsive bonds link pH, ROS, and enzyme cues to controlled release; • Achieved spatiotemporal control via programmable degradation design; • Proposed AI-guided and omics-integrated strategy for personalized repair.