Trans-endplate delivery of arginine-based poly (ester amide) for structure-preserving therapy of intervertebral disc degeneration

Intervertebral disc degeneration (IDD) remains a major cause of chronic low back pain, yet effective disease-modifying therapies are lacking. Current advanced interventions, including cell-based therapies and matrix supplementation, often disrupt disc structural integrity and fail to achieve sustained regeneration. Here, we rationally designed and synthesized a series of arginine-based poly(ester amide)s (Arg-PEAs) as endplate-penetrating biomaterials for non-direct disc therapy. Unlike conventional intradiscal injection, Arg-PEAs were administered into the adjacent vertebral bodies, enabling trans-endplate delivery into the nucleus pulposus (NP). Among them, the lead polymer 8A6S demonstrated excellent biocompatibility and efficient accumulation within the NP, as confirmed by ex vivo and in vivo imaging. Mechanistically, 8A6S suppressed IL-17 signaling by attenuating TRAF6-mediated NF-κB activation, thereby reducing inflammatory catabolism (MMP13, ADAMTS5) and restoring anabolic extracellular matrix markers (ACAN, COL2A1, SOX9). This re-establishment of matrix homeostasis promoted NP regeneration in both rat and caprine models of IDD. Collectively, this study establishes Arg-PEAs as a new class of bioactive polymers capable of trans-endplate delivery and inflammation-modulating regeneration, providing a minimally invasive and structurally preserving strategy for IDD treatment.