GM@mTG-V microspheres promote NP regeneration by reconstructing IVD biomechanics and inflammatory microenvironment.

Intervertebral disc degeneration (IVDD) has emerged as a significant global public health challenge, imposing substantial burdens on both individuals and society. Growing evidence suggests that modulating the mechanical microenvironment and alleviating inflammation in degenerated IVDs can promote tissue regeneration. In this study, we integrated natural pharmaceuticals with tissue engineering strategies to develop functionalized microspheres (GM@mTG-V) through microfluidic synthesis, where vanillin - a natural compound with anti-inflammatory and antioxidant properties - was polymerized with gelatin methacryloyl (GelMA, composed of gelatin derived from methyl acrylamide and methacrylate groups). In vitro, the functionalized microspheres not only enhanced vanillin release efficiency but also effectively suppressed inflammatory responses and oxidative stress in nucleus pulposus (NP) cells. By dynamically regulating matrix stiffness, these microspheres could remodel the mechanical microenvironment of degenerated IVD, significantly promoting extracellular matrix (ECM) secretion. In vivo, both 4 week and 8 week IVDD models demonstrated that GM@mTG-V markedly reduced tissue inflammation, accelerated ECM accumulation, and restored IVD structure, as confirmed by radiographic and histological analyses. This study verifies that GM@mTG-V promotes regeneration of degenerated IVD through dual mechanisms: stabilizing mechanical matrix stiffness and suppressing inflammatory microenvironments, providing a novel and promising therapeutic strategy for early stage IVDD.