A Bioorthogonal Nanoconcentrisome System for Epigenetic and Immunometabolic Reprogramming in Aged Bone Repair

Despite the promising potential of stem cell–based therapies in regenerative medicine, their therapeutic instability remains a major challenge, often resulting in inconsistent clinical outcomes. Achieving robust tissue regeneration requires precise control over the behavior of key cellular mediators—such as macrophages and progenitor cells—particularly at the epigenetic level, which remains an unmet need. Here, by applying single-cell RNA sequencing to systematically profile cellular heterogeneity during tissue regeneration, we identified a pronounced depletion of S-adenosylmethionine (SAM), a central epigenetic metabolite, in impaired bone tissues. We hypothesize that SAM depletion contributes to inadequate modulation of the regenerative microenvironment and associated epigenetic dysregulation. To address this, we developed a compartmentalized, fusogenic nanovesicle system (SMNV), termed the “nanoconcentrisome,” composed of SAM-loaded fusogenic liposomes encapsulating mesenchymal stem cell–derived nanovesicles (MNVs) via bio-orthogonal click chemistry. This dual-compartment architecture enables spatiotemporally controlled cellular modulation through membrane fusion. Upon fusion with macrophages, cytoplasmic delivery of SAM suppresses inflammation, followed by MNV-mediated enhancement of efferocytosis and metabolic reprogramming to establish a pro-regenerative immune niche. Concurrently, fusion with senescent stem cells restores epigenetic integrity via SAM-mediated heterochromatin reinforcement, while MNVs rejuvenate mitochondrial function and promote osteogenic differentiation. This synergistic, cell type–specific modulation significantly enhanced tissue regeneration and effectively repaired bone defects in osteoporotic rats. Collectively, our study presents a precision nanomedicine platform that integrates epigenetic and regenerative reprogramming to counteract aging-associated regenerative decline, with broad translational potential for complex multicellular diseases driven by metabolic dysfunction.