Trauma-induced bone defects and age-related osteoporosis are prevalent osteogenic disorders in which impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) remains a critical pathological challenge. Typically, BMSCs facilitate osteogenesis and increase bone mass by differentiating into osteoblasts; however, this differentiation is a high-energy process. In aging or trauma, BMSCs within the bone marrow exhibit substantial mitochondrial dysfunction, which severely limits their osteogenic potential and subsequent bone replenishment. Therefore, we developed a targeted biomimetic strategy to isolate mitochondria derived from BMSCs and formulated a membrane coating on poly(lactic-co-glycolic acid) nanoparticle cores, which were loaded with coenzyme Q10 (CoQ10) to facilitate mitochondrial repair. This engineered construct, M-NPs@CoQ10, demonstrates significantly enhanced cellular internalization and mitochondrial targeting. It exhibits superior efficacy in restoring mitochondrial function and promoting osteogenic differentiation both in vitro and in vivo. In murine models of trauma-mediated bone defects and age-induced osteoporosis, M-NPs@CoQ10 treatment achieved robust bone-recovery rates of 80% and 75%, respectively. This approach is a novel and highly effective therapeutic strategy for metabolic bone repair and related skeletal diseases.

Osteoarthritis (OA), a debilitating joint disorder affecting millions worldwide, is characterized by persistent inflammation, oxidative stress, and irreversible cartilage breakdown, yet remains without disease-modifying therapies. Inspired by natural enzymatic cascades, we developed a bioinspired nanocomposite hydrogel, N,S-doped Mn-Nb (C-CeO), that mimics endogenous antioxidant pathways to reprogram the OA microenvironment. This system combines N,S-doped Mn-Nb₂C MXene nanosheets with CeO₂ nanozymes within a boronate ester-crosslinked hydrogel, forming an “immuno-redox circuitry” with four synergistic functions: (1) cascade reactive oxygen species (ROS) scavenging via superoxide dismutase-like Mn-Nb₂C and catalase-like CeO₂, amplified by photothermal enhancement under near-infrared irradiation; (2) broad reactive nitrogen species clearance, removing peroxynitrite (ONOO⁻), nitric oxide (NO), and nitroxyl (NO⁻) to mitigate inflammation; (3) immunomodulation through Mn²⁺-activated cGAS-STING signaling, which promoted macrophage polarization toward the M2 phenotype, concomitantly reducing the levels of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α); (4) cartilage regeneration via pH/ROS-responsive simvastatin (SIM) release and nanocatalysis, upregulating SRY-box transcription factor 9 (SOX9) and Col2a1 while inhibiting matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). In a murine OA model, the system reduced synovitis by 60%, restored 80% of cartilage thickness, and suppressed osteophyte formation, outperforming single-component treatments. This strategy pioneers a “self-healing cartilage” approach by integrating nanocatalysis with immunoengineering for transformative OA therapy.