Engineered GDF11-enhanced M2 macrophage-derived nanovesicles accelerate cutaneous wound healing through PI3K/AKT–CCND1 axis

Cutaneous wound healing is strongly influenced by innate immune–stromal crosstalk. Here, we engineered GDF11-enhanced M2 macrophage–derived nanovesicles (M2G-NV) and evaluated their reparative activity, with mechanistic evidence supporting involvement of PI3K/AKT signaling and CCND1 upregulation in fibroblast responses. Macrophages were enhanced with GDF11 to produce extrusion-derived nanovesicles, which were characterized. Efficacy was validated in vitro and in a murine full-thickness wound model with topical GelMA hydrogel delivery. Pathway insights were derived from transcriptome (RNA-seq) enrichment analyses, and PI3K inhibition was used to probe the PI3K/AKT–CCND1 axis. GDF11 increased M2 polarization and yielded M2G-NV that enhanced fibroblast proliferation and migration in vitro (EdU, CCK-8, scratch and Transwell assays). In vivo, topical GelMA/M2G-NV accelerated wound closure (day 3: 24.60% vs 19.90% [GelMA/M2-NV] vs 14.92% control; day 5: 85.45% vs 81.36% vs 62.21%), with improved histology and pro-repair markers. Transcriptomic enrichment together with PI3K inhibition supported involvement of the PI3K/AKT–CCND1 axis, and GelMA encapsulation preserved vesicle bioactivity. This study introduces GDF11-enhanced M2 nanovesicles (M2G-NV) delivered topically via GelMA hydrogel. Mechanistically, our data support involvement of the PI3K/AKT–CCND1 axis in M2G-NV-induced fibroblast responses. Their cell-free nature, topical deployability, and scalability indicate promising potential for clinical translation.