A magnetic-acoustic dual-fesponsive nanoplatform for targeted PPARδ activation attenuates adolescent idiopathic scoliosis progression.

Paraspinal muscle asymmetry is a characteristic feature of adolescent idiopathic scoliosis (AIS), yet the underlying molecular mechanisms driving this degeneration remain unclear. Here, we identify the suppression of the FNDC5-associated PPARδ signaling as a key factor in the asymmetric atrophy and fibrosis of concave paraspinal muscles. We demonstrate that FNDC5 downregulation in concave myofibers is associated with impaired mitochondrial quality control and a reduction in oxidative slow-twitch fibers. Mechanistically, FNDC5 regulates mitochondrial biogenesis and fatty acid oxidation through the functionally associated nuclear receptor PPARδ. The concurrent reduction of FNDC5 and PPARδ activity leads to intracellular lipid accumulation and mitochondrial dysfunction. To overcome the systemic toxicity and hydrophobicity of PPARδ agonists, we developed a magnetic-acoustic dual-responsive nanodelivery system (LIP@PFP/GW/SPIO) for targeted delivery of the PPARδ agonist GW501516. In a bipedal AIS mouse model, this targeted intervention effectively restored mitochondrial function and muscle fiber composition, thereby retarding scoliosis progression. Overall, our findings reveal a metabolic mechanism of AIS pathogenesis and demonstrate a potential targeted therapeutic strategy for its management.