The death code in nanomessengers: Mechanisms and advances in the regulation of programmed cell death by exosomes

The process of cellular demise is fundamental for sustaining physiological balance and influencing disease outcomes. Recently, exosomes have emerged as critical nanoscale messengers in intercellular signaling, with versatile functions in orchestrating distinct patterns of programmed cell death. This article provides a comprehensive overview of exosome-mediated regulation of multiple cell death subtypes-including apoptosis, ferroptosis, necroptosis, entosis, SLFN11-related death, and ammonia-triggered death-and highlights their multifaceted contributions to immune modulation, cancer development, and tissue regeneration. This article integrates Ongoing studies on the functions of exosomes in various cell death modes from the perspectives of signaling pathways, epigenetic regulation, and metabolic pathways. It focuses on the molecular mechanisms by which exosomes, through bioactive cargos such as miRNA, lncRNA, circRNA, and proteins, influence key signaling axes, including PI3K/AKT, Fas/FasL, p53, SLC7A11/GPX4, RIPK1/RIPK3/MLKL, Keap1/Nrf2, STAT6, and TAM receptors. Notably, exosomes demonstrate powerful specificity and systemic regulatory potential, particularly in the regulation of iron homeostasis, lipid peroxidation, immune polarization, and entosis. As a "nano delivery system" for intracellular and extracellular signals, exosomes not only regulate cell death modalities but also offer new strategic possibilities for disease intervention. In the future, exosome-mediated cell death regulation is expected to be used in the development of precision therapeutic tools, improving the intervention efficiency in tumors, immune diseases, and metabolic disorders. In summary, a thorough insight of the mechanisms by which exosomes regulate cell death is crucial for elucidating the fundamental basis of disease development and for translational medical applications.