PLGA-microspheres carried circ_0003251 alleviate intervertebral disc degeneration via the miR-637/AKT1 axis.

BACKGROUND: Circular RNA (circRNA) plays a pivotal role in regulating nucleus pulposus cells (NPCs) function, making it a promising therapeutic target for intervertebral disc degeneration (IDD). This study aimed to identify circRNA closely associated with IDD and assess their potential as therapeutic target. METHODS: Circ_0003251 was identified via circRNA sequencing and validated in degenerated human nucleus pulposus (NP) tissues. Its properties were characterized using Sanger sequencing, oligo(dT) primers, RNase R treatment, and fluorescence in situ hybridization. Functional experiments assessed its role in vitro, while molecular mechanisms were explored through luciferase reporter assays, RNA-binding protein immunoprecipitation, and immunofluorescence. To assess therapeutic potential, circ_0003251 was encapsulated in PLGA (poly(lactic-co-glycolic acid)) microspheres (MS) and evaluated in vitro and in vivo. RESULTS: Circ_0003251 expression was significantly downregulated in degenerated NPCs and NP tissues. Its upregulation enhanced NPCs proliferation, extracellular matrix synthesis, and reduced apoptosis. Mechanistically, circ_0003251 acted as a miR-637 sponge, inhibiting AKT1 suppression and alleviating NPCs degeneration. PLGA MS successfully delivered circ_0003251, enhancing its therapeutic effect and delaying IDD in vivo. CONCLUSION: Circ_0003251 was a promising biomarker and therapeutic target for IDD. PLGA MS delivery ensured effective application, offering a novel strategy for IDD treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-06800-z.