Myogenic nano-adjuvant for orthopedic-related sarcopenia via mitochondrial homeostasis modulation in macrophage-myosatellite metabolic crosstalk.

The decline in skeletal muscle mass and muscle strength linked to aging, also known as sarcopenia, is strongly associated with disability, traumatic injury, and metabolic disease in patients. Meanwhile, sarcopenia increases the risk of adverse orthopedic perioperative complications including implant dislocation, infection, loosening, and poor wound healing. Mitochondrial dyshomeostasis in the immune-myosatellite metabolic crosstalk is one of the major pathological factors in sarcopenia. To reduce the incidence of orthopedic perioperative complications in patients, we designed and developed a nano-adjuvant based on two-dimensional layer double hydroxide (LDH) for sustained improvement of systemic and orthopedic-related sarcopenia. Construction of MgAlCo-LDH@UA (MACL@UA) nano-adjuvant was performed by introducing cobalt in magnesium-aluminum LDH and further loading urolithin A (UA). The release of magnesium ions and UA promoted myocyte proliferation, angiogenesis and improved mitochondrial homeostasis. Al acted as an immunomodulatory adjuvant to enhance the metabolic crosstalk between macrophages and myosatellite cells, and prompted macrophage-derived glutamine nourishment. Animal experiments confirmed that vaccination with MACL@UA in systemic sarcopenia and intensive orthopedic perioperative vaccination with MACL@UA significantly enhanced quadriceps muscle mass in rats. This nano-adjuvant offers a solution for long-term improvement of sarcopenia and short-term significant reduction of orthopedic perioperative complications in patients, with promising prospects for clinical application and commercial translation.