Tendinopathy is a prevalent degenerative musculoskeletal disorder that can progress to heterotopic ossification (HO), ultimately resulting in tissue stiffening and biomechanical deterioration. However, effective early-stage therapeutic strategies to prevent pathological ossification remain limited. In this study, taking advantage of clinical sequencing and preliminary in vivo results that uncovered an early osteoclast-driven target in tendon HO, we engineered a multifunctional zwitterionic nanogel entrapping siponimod (T-S/A nanogel@siponimod) for the potent and selective blockade of osteoclast maturation. The nanogel was prepared by copolymerization of sulfobetaine methacrylate (SBMA) and acrylic acid (AA), and subsequently conjugated to an anti-type I collagen antibody. This design endowed the nanogel with tendon-specific targeting, resistance to nonspecific protein adsorption, and pH-responsive drug release under acidic conditions. In vitro experiments and transcriptomic analyses showed that targeted siponimod delivery markedly inhibited RANKL-induced osteoclastogenesis via blockade of the NF-κB signaling pathway. This intracellular inhibition acted crucially by downregulating the clastokine growth differentiation factor 3 (GDF3), which in turn dampened the pro-osteogenic secretome and abolished the aberrant osteoclast-tendon stem progenitor cell (TSPC) crosstalk. In vivo evaluation in a rat model of tendinopathy-induced HO identified the initial 4 weeks after injury as a critical therapeutic window. Early administration of T-S/A nanogel@siponimod effectively inhibited heterotopic bone formation, reduced the volume of mineralized tissue, and maintained a better-organized tendon tissue structure. Collectively, this study presents a highly specific nanotherapeutic strategy that prevents tendon HO by silencing early osteoclast-driven remodeling. This targeted strategy offers a promising approach for treating local microenvironment-driven musculoskeletal diseases.
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