Biomimetic nanospheres as a therapeutic intervention for disrupting the infection-ischemia cycle in ischemic limbs

Atherosclerosis-induced critical limb ischemia, characterized by impaired neovascularization and high susceptibility to infection, remains a major therapeutic challenge. Here, we developed a fungi-like biomimetic nanoparticle-based delivery system by loading adipose-derived stem cell exosomes (ADSC-exos) into chitosan (CS) via flash nanocomplexation (FNC), yielding ADSC-exo@CS nanoparticles. This approach leveraged the electrostatic interactions to complex exosomes with CS, thereby enhancing exosome stability and cellular uptake, while also capitalizing on the inherent antibacterial properties of CS shell. The resulting ADSC-exo@CS nanoparticles exhibited excellent structural stability for over 20 days and achieved a 2.9-fold increase in cellular internalization compared to free ADSC-exos. Both in vitro and in vivo assessments demonstrated that ADSC-exo@CS possessed strong antibacterial activity, promoted angiogenesis, and modulated immune responses by facilitating macrophage polarization toward the M2 phenotype. In a murine model of hindlimb ischemia, ADSC-exo@CS treatment led to rapid restoration of blood perfusion, reduced tissue fibrosis, and a 100% limb salvage rate, significantly outperforming the control and monotherapy groups. These results highlight a biomimetic synergistic therapeutic strategy that promotes angiogenesis while preventing infection, precisely disrupting the vicious cycle and facilitating in situ repair in ischemic limb disease with a minimally invasive and scalable approach.