Matrix-Bound Nanovesicles as Tissue-Specific Signaling Hubs for Immunomodulation and Precision Regenerative Medicine.

The evolution of regenerative medicine has repositioned the extracellular matrix (ECM) from a passive structural scaffold to a dynamic signaling hub that dictates host immunity and tissue remodeling. A critical driver of this bioactivity is the matrix-bound nanovesicle (MBV), a distinct subclass of extracellular vesicles (EVs) physically embedded within collagen fibers. Unlike fluid-phase EVs, MBVs exhibit unique release kinetics triggered by matrix degradation and possess tissue-specific molecular signatures that dictate their therapeutic potential. This review evaluates the biogenesis, isolation, and cellular tropism of MBVs, highlighting the macrophage as a central mediator of their immunomodulatory effects. We propose a "precision medicine" framework for matching MBV tissue sources-ranging from pro-angiogenic small intestinal submucosa to anti-angiogenic cartilage-to the specific pathological requirements of the target injury. Furthermore, we discuss post-harvest engineering strategies, including surface functionalization via click chemistry and exogenous cargo loading, to enhance MBV targeting and potency. Finally, we address the translational hurdles of protocol standardization and pharmacokinetic characterization required to transition MBVs into a scalable, cell-free platform for regenerative therapy.