Spatiotemporally programmed VEGF/IL-4 delivery via HMSNs enhances endothelialization and immune-mediated matrix remodeling in acellular vascular grafts.

Delayed endothelialization and inadequate matrix remodeling remain major obstacles in the development of small-diameter vascular grafts (SDVGs; <6 mm). To address these challenges, we developed an immunomodulatory tissue-engineered vascular graft (iTEVG) by integrating hollow mesoporous silica nanoparticles (HMSNs) with tailored mesopore sizes as delivery carriers for immunoregulatory factors. VEGF was selectively immobilized on the intimal surface, while the adventitia incorporated a sequential release system for VEGF and IL-4. VEGF exhibited rapid release (64.04 ± 4.44 % in 7 days), promoting monocyte recruitment and adventitial neovascularization, while IL-4 showed sustained release (65.94 ± 2.06 % over 28 days), driving long-term M2 macrophage polarization. In rats, iTEVGs achieved 88 % endothelial coverage and smooth muscle cell infiltration within 1 month, full-thickness cellularization with a complete trilaminar structure by 3 months, and maintained mechanical integrity without aneurysm formation up to 6 months. This spatially partitioned platform, built on an acellular vascular scaffold, enables precise spatiotemporal regulation of the immune microenvironment and offers a design paradigm that synergistically promotes endothelialization and vascular matrix remodeling. The "intima-targeted regeneration and adventitia-sequential-release" strategy provides a promising template for SDVG design that may be extended to other complex organ constructs.