Abstract

Tendinopathy is a common condition that causes long-term pain. The inflammatory microenvironment (inflamed soil) promotes the ingrowth of sensory nerves (a key pain trigger) and induces functional impairments in tendon stem/progenitor cells (TSPCs) (dysfunctional seeds). These interconnected processes collectively drive the progression of tendinopathy, which is frequently accompanied by persistent pain. Here, we develop a multifunctional nanoplatform (MSM-DTM) by integrating macrophage-sensory neuron hybrid membrane vesicles (MSM) and decellularized tendon matrix (DTM). MSM, fused from macrophage and sensory neuron membranes, efficiently binds multiple inflammatory cytokines and neuropeptides, thereby reprogramming the inflammatory microenvironment. Moreover, MSM breaks the vicious cycle of inflammation-induced senescence and prevents TSPCs aging. DTM promotes tenogenic differentiation and migration of TSPCs, improving tendon regeneration. In vivo , MSM-DTM improves collagen alignment, regulates macrophage polarization, alleviates pain, and enhances tendon functional recovery. MSM-DTM disrupts the inflammation-senescence positive feedback loop and reconstructs a pro-regenerative microenvironment, offering a promising strategy for tendinopathy.