Targeting mitochondrial copper(II) for epigenetic modulation of macrophage polarization to prevent senile osteoporosis

Epigenetic regulation governs macrophage polarization during inflamm-aging, influencing age-related bone loss. Mitochondrial copper(II) drives pro-inflammatory epigenetic remodeling in bone marrow-derived macrophages (BMDMs), yet its mechanistic role remains unclear. Here, we developed ALN/HA@TPP@TM Lipo, a bone/mitochondria-targeted liposomal system delivering the copper chelator tetrathiomolybdate, to investigate mitochondrial copper(II)'s epigenetic impact in senile osteoporosis. Aged mice exhibited elevated mitochondrial copper(II) levels in BMDMs, correlating with M1 polarization dominance and bone loss. Mechanistically, mitochondrial copper(II) modulates H3K27ac, an epigenetic histone mark, to enhance chromatin accessibility for HIF-1α, amplifying pro-inflammatory cytokine transcription (e.g., TNF-α, IL-1β) and sustaining osteoporotic inflammation. Targeted copper(II) chelation via ALN/HA@TPP@TM Lipo reduced H3K27ac enrichment at HIF-1α promoters, suppressed M1 polarization, and shifted macrophages toward anti-inflammatory M2 phenotypes. This epigenetic reprogramming restored BMSC osteogenesis in co-cultures and attenuated bone loss in aged mice. Our findings position mitochondrial copper(II) as a pivotal regulator of inflamm-aging-associated osteoporosis, offering a dual-targeted therapeutic strategy to disrupt pro-inflammatory epigenetic circuits and mitigate senile bone degeneration. • A dual-targeted liposome (ALN/HA@TPP@TM Lipo) was engineered for bone/mitochondria-specific delivery of copper chelator TM, enabling pH-responsive release and epigenetic reprogramming of macrophages. • Mitochondrial copper(II) was identified as an epigenetic regulator driving H3K27ac-mediated chromatin remodeling to amplify HIF-1α signaling and pro-inflammatory macrophage polarization in senile osteoporosis. • Targeted copper(II) chelation shifted M1-to-M2 macrophage polarization, restored BMSC osteogenesis in cocultures, and attenuated bone loss in aged mice by suppressing inflamm-aging circuits.