Musculoskeletal organoids-on-chip uncover muscle–bone communication under intermittent hypoxia

Muscle and bone have intimate biochemical associations spatiotemporally. Yet, the muscle-bone dynamic alterations under intermittent hypoxia (IH) remain unclear, primarily due to the lack of suitable microphysiological models. Herein, we developed a novel musculoskeletal organoids-on-chip (MSK OoC), advancing an integrated study of muscle-bone biochemical communication and personalized interventional strategies. Within this MSK OoC, muscle organoids (MOs) replicate <i>in vivo</i> micro-architecture, while bone organoids mimic both the formation and remodeling processes. Utilizing MSK OoC, we discovered that IH-induced muscle pathology suppressed osteogenesis but stimulated osteoclastogenesis. The mitochondria protein Sirt3 in muscle played a pivotal role in regulating bone metabolism via myokine Cxcl5. Besides, mitochondria-targeting sequence-mediated Sirt3 overexpression in MOs effectively reversed bone deterioration. To validate mitochondria-targeted therapeutics, a Janus silica nano-vehicle was adopted to deliver resveratrol upon MSK OoC, effectively rescuing the pathological muscle-bone dysfunction. This study highlights the potential of the MSK OoC platform for investigating interorgan communication and developing precise nanomedicine therapies.