Nanogel-Based Precision Bone Regeneration: Rational Design, Biological Barrier Penetration, and Osteoporotic Microenvironment Remodeling.

The pathogenesis of osteoporosis is primarily associated with impaired communication between osteoblasts and osteoclasts, leading to disrupted bone homeostasis. Conventional biomaterials mainly rely on macroscopic structural support and are limited in their ability to precisely regulate the complex bone microenvironment and overcome biological barriers. As representative soft matter nanoplatforms, nanogels possess unique viscoelastic mechanical properties and adaptive biointerfacial properties, offering new opportunities to overcome physical barriers within bone tissues. Moving beyond previous studies that primarily focused on the passive structural support provided by macroscopic hydrogels, this review presents a micro-nano-bio interfacial perspective to systematically elucidate the roles of nanogels in precision therapy for bone disorders. Considering the spatial constraints of the lacunar-canalicular system (LCS), with canalicular diameters of approximately 100-300 nm, we highlight how the stress relaxation behavior and deformation modulus of nanogels jointly determine their migration and penetration efficiency within confined spaces. Furthermore, nanogels can function as dynamic biomimetic systems that sense alterations in the bone microenvironment and actively regulate immune and metabolic homeostasis within bone tissue. This review summarizes engineering strategies for nanogel development, including optimization of network architectures, hierarchical surface targeting, and multi-responsive drug release mechanisms. In addition, the effects of protein corona formation and biological barriers on the in vivo fate and therapeutic performance of nanogels are critically discussed. Finally, from a translational perspective, we evaluate the therapeutic potential and key challenges of nanogels in precision bone regeneration and propose design principles for next-generation bone-targeted nanomedicines based on mechanical adaptation, biointerface engineering, and intelligent responsiveness.