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

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.