M2 macrophage-derived exosomes deliver NGF-modified mRNA to promote comprehensive corneal repair.

The cornea is a unique tissue vital for vision but susceptible to various injuries. Given this complexity, effective regeneration following severe damage requires the coordinated restoration of multiple tissue components, underscoring the need for innovative therapeutic strategies. mRNA technology has emerged as a transformative platform for protein delivery and therapeutic intervention. Chemically modified mRNA (modRNA), with its enhanced stability and reduced immunogenicity, enables transient yet highly efficient protein expression, positioning it as a powerful tool for therapeutic applications. Successful mRNA delivery requires optimized vectors, among which exosomes represent ideal carriers due to their natural anti-inflammatory and reparative properties, high loading capacity, and intrinsic targeting ability. Here, we harnessed M2 macrophage-derived exosomes (M2-Exos) to deliver NGF modRNA (modNGF) for multidimensional corneal repair. This combined delivery system demonstrated robust protein expression, simultaneously promoting tissue regeneration while suppressing inflammation and neovascularization in alkali-burned corneas. Single-cell RNA sequencing further revealed that the system effectively restores injury-induced cellular heterogeneity, promotes epithelial regeneration, reprograms immune cells, and enhances corneal nerve regeneration through neuroglial cell proliferation and modulation. Our findings underscore the synergistic therapeutic effects of M2-Exos and modNGF, establishing this innovative delivery platform as a promising strategy for ocular surface diseases and broader regenerative medicine applications.