Tissue-specific matrix-bound nanovesicles regulate the immunoregulatory progress of biological mesh-aided abdominal hernia repair

Consensus on abdominal hernia treatment with biological meshes remains elusive, largely due to variable and dynamic responses that dictate extracellular matrix (ECM) remodeling outcomes. Matrix-bound nanovesicles (MBVs) are ECM-embedded bioactive cues that govern cell-mesh crosstalk, whereas their tissue-specific functions in immunomodulatory repair remain poorly understood. Herein, MBVs were isolated from clinically used small intestinal submucosa (SIS) and urinary bladder matrix (UBM)-SIS (UBM-SIS) meshes to investigate their differential immunomodulation during hernia repair. SIS MBVs promoted angiogenesis via ERK1/2 activation, while UBM MBVs favored anti-inflammatory macrophage polarization through transforming growth factor-β1(TGF-β1) signaling pathways, showing synergistic effects in combination. In the repair of a full-thickness rat model, UBM-SIS meshes elicited milder early inflammation than SIS meshes. However, the superior immunomodulation of UBM was compromised with the progressive exposure of SIS interlayer. Conversely, SIS meshes initially triggered pronounced inflammation but switched to an anti-inflammatory state after 4 weeks, facilitating tissue integration over 8 weeks through prevailing neovascularization. The ECM-driven response in distinct microenvironments closely aligned with the spatiotemporal release of respective MBVs, with mechanistic analyses corroborating their functional relevance in orchestrating reciprocal pro/anti-inflammatory and remodeling signals. Investigating tissue-specific MBVs offers insights into their roles in hernia repair and highlights emerging therapeutic potential in regenerative applications. Schematic illustration of matrix-bound nanovesicle (MBV)-mediated immunomodulatory mechanisms in biological mesh–aided abdominal hernia repair. MBVs embedded within extracellular matrix (ECM) regulate cell–matrix crosstalk through dynamic release and state-dependent signaling under distinct microenvironments. Tissue-specific MBVs derived from porcine small intestinal submucosa (SIS) and urinary bladder matrix (UBM) exhibit divergent immunomodulatory functions, differentially governing macrophage polarization, angiogenesis, and ECM remodeling in a rat abdominal wall defect model. Through cellular internalization and delivery of bioactive cargos, MBVs orchestrate downstream signaling pathways and act as key immunoregulatory determinants of biological mesh-guided tissue repair, with potential implications for cross-disciplinary biomaterial applications. • Matrix-bound nanovesicles (MBVs) act as immunoregulatory cues in biological mesh-aided abdominal wall defect repair. • Tissue-specific MBVs from porcine-derived ECM exhibit distinct immunomodulatory profiles within cell-matrix interactions. • Spatial and temporal MBV release drives divergent ECM remodeling in vivo . • Targeting specific MBVs provides a strategy to engineer next-generation immunomodulatory meshes.