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.