Microalgae-Macrophage Hybrid Exosome-like Nanovesicles for Mitophagy Restoration and Wound Regeneration in Aging

The wound healing capacity in the elderly is significantly impaired, leading to increased susceptibility to inflammation and infection, and potentially contributing to reduced lifespan. In aged wounds, dysfunctional mitophagy in senescent cells (SnCs) results in the persistent release of pro-inflammatory cytokines, fostering a chronic inflammatory microenvironment that further delays tissue repair. To address this challenge, we developed a thermosensitive hydrogel loaded with hybrid exosome-like nanovesicles to enhance wound healing in aging. These hybrid nanovesicles (termed SP-M2-ENs) were generated by extrusion-mediated fusion of spirulina-derived exosome-like nanovesicles (SP-ENs) with M2 macrophage-derived exosome-like nanovesicles (M2-ENs). SP-ENs are rich in phycocyanin and exhibit strong antioxidant activity, whereas M2-ENs carry multiple anti-inflammatory cytokines and growth factors. This synergistic combination endows the hybrid system with enhanced anti-inflammatory and regenerative capabilities. To ensure sustained release and conformability to irregular wound topographies, the hybrid nanovesicles were encapsulated within a thermosensitive hydrogel (PF-127 gel), forming the final therapeutic construct, designated SP-M2-ENs@Gel. Comprehensive in vitro and in vivo studies demonstrated that SP-M2-ENs@Gel effectively scavenges reactive oxygen species (ROS), promotes tissue regeneration, stimulates angiogenesis, modulates macrophage polarization toward a reparative phenotype, and enables prolonged delivery of therapeutic agents. Specifically, SP-M2-ENs@Gel accelerates healing in aged wounds by restoring mitophagy function in senescent cells, thereby alleviating chronic inflammation. Collectively, this platform represents a promising strategy for overcoming senescence-impaired wound repair, highlighting the clinical translatability of engineered exosome-based therapies in regenerative medicine.