Supramolecular delivery of senolytics enables targeted anti-senescence therapy and accelerated fracture healing

Current clinical management of fractures relies largely on surgical intervention and systemic pharmacotherapy, both of which are frequently associated with side effects and largely neglect early microenvironmental abnormalities. Precise elimination of senescent cells at the early stage may offer a more efficient means of restoring microenvironmental homeostasis and resetting regenerative dynamics. To this end, we designed and synthesized a multifunctional supramolecular nanoplatform, Asp₁₀SAC4A, based on combination of host-guest recognition and self-assembly to simultaneously address three fundamental challenges in selectively eliminating senescent cells at the fracture site: inadequate targeting, insufficient responsiveness, and poor coordination of multi-drug delivery. The platform consists of an azocalix [4]arene modified with a deca-aspartate (Asp₁₀) peptide for selective binding to newly exposed hydroxyapatite at fracture sites, enabling active localization. Simultaneously, Dasatinib and Quercetin are co-loaded in a controlled ratio, and triggered for rapid release through the hypoxia-responsive mechanism of the azo groups, achieving microenvironment-specific "source-clearing" therapy. This strategy significantly alleviates inflammation, enhances osteogenesis and accelerates fracture healing. These results highlight the crucial role of selectively targeting senescent cells in the early phase of fracture and offer an innovative therapeutic approach that improves treatment efficiency and prognosis. Overall, this study aims to establish a fracture-site-activated senolytic delivery strategy that integrates fracture targeting, hypoxia-triggered release, and combination therapy, thereby enabling precise early-stage anti-senescence intervention to accelerate fracture healing.