Spontaneous phase separation-driven Janus hydrogel spatiotemporally orchestrates the fibrotic progression for functional tendon regeneration.

Postoperative tendon regeneration hinges on the precise spatiotemporal orchestration of fibrotic progression, aberrant fibrogenesis instead drives pathological adhesion formation and impairs functional recovery. However, current strategies often target isolated aspects of fibrotic progression and rely on complex fabrication procedures. Here, we engineer a Janus hydrogel (SPS-JH) via spontaneous phase separation-driven stratification and photopolymerization of methacrylated hyaluronic acid (HAM) and poly(lactide)-b-poly(propylene glycol)-b-poly(lactide) dimethacrylate (PLD). This innate water/oil demixing yields a Janus architecture in which the outer HAM layer establishes a lubricated anti-adhesion interface, while the inner PLD layer confers durable mechanical reinforcement. Critically, the SPS-JH decodes the temporal hierarchy of tendon repair: the MMP-2-degradable HAM layer releases COX-2 siRNA to silence fibroblast hyperactivation during early inflammation, whereas the PLD matrix sustains niclosamide (NEN) release to polarize macrophages during inflammation and suppress fibrogenesis during proliferation. In rats with Achilles tendon injury, SPS-JH reduces peritendinous adhesions and promotes biomechanically competent, functional tendon regeneration. Transcriptomic analysis reveals coordinated activation of mechanotransduction and tissue remodeling programs accompanied by suppressed fibrogenic signaling. This work establishes a structurally minimalist yet biologically sophisticated paradigm wherein spontaneous phase separation coordinates with the dynamic fibrotic progression to enable functional tendon regeneration.