Abstract <p>Diabetic wound healing remains a clinical challenge due to chronic inflammation, impaired angiogenesis, and delayed tissue regeneration. Adipose-derived stem cell exosomes (ADSC-Exosomes) have emerged as promising nanotherapeutics owing to their immunomodulatory and regenerative properties. Hypoxia-preconditioned ADSC-Exosomes significantly enhance angiogenesis, with studies reporting up to a 2.5-fold increase in VEGF and 60% activation of the PI3K/Akt pathway. In diabetic murine models, exosome treatment accelerates wound closure by 30–45% compared to controls. However, limitations such as low exosome yield (~ 1–5&#xa0;µg/mL), short in vivo half-life (&lt; 6&#xa0;h), and poor targeting restrict clinical utility. Electrospun nanofiber scaffolds offer a synergistic platform, mimicking the extracellular matrix and enhancing exosome stability, retention (up to 80% over 48&#xa0;h), and sustained release. Nevertheless, current studies show variable exosome loading efficiency (20–60%) and limited understanding of release kinetics under diabetic conditions. The complex interaction between exosome-derived signaling and the chronic wound microenvironment remains underexplored. This review summarizes recent advances in ADSC-Exosome-based nanotherapeutics, focusing on hypoxia preconditioning, scaffold integration, and delivery optimization. It also highlights innovative strategies including bioreactor-based exosome production (yield increased up to tenfold), CRISPR/Cas-mediated cargo engineering, and AI-assisted scaffold design as emerging solutions to current barriers. Addressing these challenges is essential to unlock the full therapeutic potential of exosome-functionalized smart biomaterials for diabetic wound healing.</p> Lay Summary <p>Diabetic wounds, especially foot ulcers, are difficult to heal due to poor blood circulation, chronic inflammation, and reduced tissue repair. This leads to a higher risk of infections and even amputations. Traditional treatments often fall short, prompting the need for innovative approaches. This research explores a new treatment strategy using exosomes, tiny healing messengers naturally released by stem cells, and nanofiber scaffolds, which mimic the body’s tissue structure. This review focuses on exosomes derived from adipose tissue stem cells (ADSCs), particularly when these cells are cultured under low-oxygen (hypoxic) conditions. Hypoxia enhances the potency of exosomes by amplifying their capacity to stimulate new blood vessel formation and mitigate inflammation. However, exosomes alone break down quickly and do not stay in the wound long enough. To overcome this, the study uses ultra-thin nanofibers that can carry and slowly release exosomes directly at the wound site, offering better healing over time. These fibers are designed to support tissue growth, prevent infection, and release the exosomes in a controlled manner. By combining hypoxia-enhanced exosomes with smart nanofibers, the research shows improved healing in diabetic wounds. This approach offers a promising and targeted solution that could one day be used in clinical settings to help patients with chronic wounds heal faster and more effectively.</p> Graphical Abstract <p></p>