Improving tendon repair through spatiotemporal modulation of TGF-β1 expression using an ultrasound-responsive hydrogel carrying siRNA-loaded nanoparticles

Adhesion is a common complication during healing of injured tendons. TGF-β1 has a dual role in tendon healing, promoting tendon healing in the early stage, whereas its continued expression in the mid and late stages can lead to adhesion formation. Therefore, precise regulation of TGF-β1 expression to inhibit adhesion formation without compromising tendon healing strength may be an important strategy for enhancing tendon repair. Here, we designed an ultrasound-responsive hydrogel (URH) for carrying siRNA-loaded nanoparticles. This hydrogel enables the controlled release of encapsulated drugs in specific timeframes and locations under the influence of medical ultrasound (M-US), improving drug targeting efficiency. The URH was composed of sodium alginate modified with thioketal (tK) [which can be cleaved by reactive oxygen species (ROS)], TiO₂, CaCl₂, and siRNA-loaded nanoparticles. TiO₂ generates ROS upon ultrasound treatment. Nanoparticles are loaded with siRNAs to inhibit TGF-β1 expression. This URH system exhibited good stability and biocompatibility in vitro and in vivo, and could be degraded by M-US to release functional siRNA-loaded nanoparticles. In a rat flexor tendon injury model, the application of this system could effectively induce the tendon adhesion formation without compromising the tendon healing strength. Based on these results, URH system represents a promising therapeutic strategy for the repair of injured tendons. STATEMENT OF SIGNIFICANCE: 1. An ultrasound-responsive hydrogel carrying nanoparticles was successfully prepared, and the hydrogel can be degraded by ultrasound to release nanoparticles in a controlled manner when needed. 2. TGF-β1 siRNA loaded nanoparticles were encapsulated in this ultrasound-responsive hydrogel, which can be applied in vivo to dynamically regulate TGF-β1 expression in adhesion tissues. 3. This ultrasound-responsive hydrogel carrying TGF-β1 siRNA loaded nanoparticles can effectively limit adhesion formation without affecting tendon healing, which is a promising strategy for the treatment of injured tendons.