Intervertebral disc degeneration (IVDD) is a leading cause of discogenic low back pain, contributing significantly to global disability and economic burden. Current treatments provide only short-term pain relief without addressing the underlying pathogenesis. Herein we report engineering of biomimetic therapies for IVDD guided by single-cell RNA-sequencing data from human nucleus pulposus tissues, along with validation using animal models. In-depth analyses revealed the critical role of mitochondrial dysfunction in fibrotic phenotype polarization of nucleus pulposus cells (NPCs) during IVDD progression. Consequently, mitochondrial transplantation was proposed as a novel therapeutic strategy. Transplanted exogeneous mitochondria improved mitochondrial quality control in NPCs under pathological conditions, following endocytosis, separate distribution or fusion with endogenous mitochondria, and transfer to neighboring cells by tunneling nanotubes. Correspondingly, intradiscal mitochondrial transplantation significantly delayed puncture-induced IVDD progression in rats, demonstrating efficacy in maintaining mitochondrial homeostasis and alleviating pathological abnormalities. Furthermore, exogenous mitochondria were engineered with a bioactive, mitochondrial-targeting macromolecule to impart anti-oxidative and anti-inflammatory activities. The obtained multi-bioactive biotherapy exhibited significantly enhanced benefits in IVDD treatment, in terms of reversing IVDD progression and restoring structural integrity through the mtDNA/SPARC-STING signaling pathways. Overall, our engineered mitochondrial therapies hold great promise for treating IVDD and other musculoskeletal diseases linked to mitochondrial dysfunction.