Root-system-inspired core-shell microneedles enable spatiotemporal sequential therapy via ROS scavenging, angiogenesis, and capillary-driven lipid removal for enhanced fat graft survival.

BACKGROUND: Autologous fat grafting is widely used in reconstructive and esthetic surgery, but its clinical outcomes are limited by early ischemia-hypoxia, oxidative stress, delayed vascularization, and subsequent lipid accumulation-induced inflammation. Current therapeutic strategies generally focus on single-stage regulation and lack temporal coordination with the dynamic pathological evolution of transplanted adipose tissue. Here, we developed a root system-inspired core-shell microneedle (MN) platform capable of sequentially regulating the graft microenvironment through early vascular promotion and later lipid removal. METHODS: Vascular endothelial growth factor-loaded modified silk fibroin methacryloyl/grooved poly(lactic-co-glycolic acid) core-shell MNs (VEGF@mSF/gPLGA-MNs) were fabricated by integrating a reactive oxygen species (ROS)-responsive mSF shell with a lipid-adsorbing gPLGA core. The physicochemical properties, ROS scavenging ability, VEGF release behavior, and lipid adsorption capacity of the MNs were systematically characterized. Their biological effects were evaluated using in vitro cellular assays and a mouse autologous fat grafting model. Graft survival, vascularization, inflammatory regulation, and adipose remodeling and the underlying molecular mechanisms were assessed by imaging, histological analyses, immunofluorescence staining, ribonucleic acid sequencing, and western blotting. RESULTS: The mSF shell rapidly responded to oxidative stress and degraded during the early stage after implantation, enabling localized VEGF release while alleviating ROS-induced cellular damage. Following shell degradation, the exposed gPLGA core facilitated directional lipid adsorption owing to its lipophilic properties and groove-mediated capillary transport. In vitro studies demonstrated improved endothelial migration, angiogenesis, ROS clearance, and mitochondrial protection. In a mouse fat graft model, VEGF@mSF/gPLGA-MNs significantly improved graft retention, reduced cystic degeneration and fibrosis, increased vascularization, and promoted adipose tissue remodeling. Transcriptomic and protein analyses revealed that lipid metabolism-related pathways, including PPAR signaling, were activated, and that inflammatory pathways, such as the NF-κB, TNF, IL-17, and toll-like receptor signaling pathways, were suppressed. CONCLUSIONS: The root system-inspired VEGF@mSF/gPLGA-MN platform enables spatiotemporally sequential regulation of the fat graft microenvironment by coordinating early vascular reconstruction with subsequent lipid clearance. This strategy provides a promising approach for improving fat graft survival and may offer a generalizable paradigm for regenerative therapies involving dynamic pathological transitions.