Thermosensitive Liposome-Loaded Hydrogels Enable Mechano-Chemical Cascade Therapy for Promoting Angiogenesis

Pharmacological activation of selective biophysical or chemical signaling pathways is known to regulate angiogenesis; however, whether these cues can be modulated in a temporally coordinated, cascade-like manner to generate stable and functional vascular networks remains unclear, particularly in the ischemic microenvironment. Here, we demonstrate a mechanochemical cascade in which TRPV4 (transient receptor potential vanilloid 4)-mediated mechanosensing initiates endothelial activation, followed by platelet-derived growth factor-BB (PDGF-BB) signaling that drives vascular formation and maturation. Specifically, we engineered a thermosensitive liposome-loaded hydrogel that responds to endogenous temperature changes to achieve precise, temporally ordered release of angiogenic initiators and stabilizing factors. In a murine critical limb ischemia model, early release of the TRPV4 agonist GSK1016790A initiated angiogenic activation, accompanied by gradual local temperature recovery during ischemic repair, which provided the expected thermal window for delayed PDGF-BB release to support nascent vessel maturation. The thermo-adaptive cascade release achieved 91.5% restoration of limb perfusion, coupled with a substantial surge in mature vessel density, yielding superior functional recovery that outperforms simultaneous therapy. Our findings not only illuminate the transformative potential of mechano-chemical synergistic therapies for ischemic diseases but also unveil the pivotal role of temporally orchestrated pro-angiogenic and stabilizing signals in driving robust, self-regulated vascular regeneration.