A bioorthogonal nanoconcentrisome system for epigenetic and immunometabolic reprogramming of tissue regeneration in...

Stem cell-based therapies show promise for tissue regeneration but are limited by therapeutic instability, particularly in aged tissues. Here, multi-omics profiling of regenerating bone reveals marked depletion of S-adenosylmethionine (SAM), indicating epigenetic dysregulation associated with impaired repair. To address this, we develop a spatially compartmentalized, fusogenic nanovesicle system (SMNV), termed a "nanoconcentrisome," composed of SAM-loaded fusogenic liposomes encapsulating mesenchymal stem cell-derived nanovesicles (MNV). This dual-compartment architecture facilitates cytosolic delivery of cargos through membrane fusion with limited lysosomal involvement. In macrophages, SMNV attenuates inflammatory activation and promotes efferocytosis and metabolic reprogramming, while in senescent stem cells it enhances epigenetic integrity, mitochondrial function and osteogenic differentiation. Through coordinated modulation of immune and progenitor cell states, SMNV significantly enhances tissue regeneration and effectively repairs bone defects in aged female rats, highlighting a precision nanomedicine platform that integrates metabolic-epigenetic regulation with cell-free regenerative signaling to counteract ageing-associated regenerative decline.