Characterized by a cascade of profound changes in nucleus pulposus (NP) cells, extracellular matrix (ECM), and biomechanics, intervertebral disc degeneration is a common multifactorial condition that may lead to various degenerative lumbar disorders. Therapeutic strategies targeting a single factor have shown limited efficacy in treating disc degeneration, and approaches that address multiple pathological ingredients are barely reported. In this study, engineered cell membrane-encapsulated keratin nanoparticles are developed to simultaneously alleviate NP cell senescence and promote ECM remodeling. To achieve this, salivary acid glycoengineered adipose mesenchymal stem cell membranes are used to coat keratin, a core protein for structural support and cellular protection. The synthesized cell membrane-coated keratin nanoparticles (MKNs) effectively protected mitochondrial integrity in NP cells from oxidative stress-induced damage. Moreover, MKNs modulate mitochondrial metabolism and attenuate NP cell senescence. In addition, MKNs activate integrins at the cell membrane and enhance the interactions between NP cells and ECM, resulting in increased ECM anabolism and decreased catabolism. The proposed multi-targeted strategy to block the degenerative cycle inside the disc is efficacious for treating disc degeneration and may have the potential for clinical application.