Beyond cell replacement: restoring organelle homeostasis as the next frontier of regenerative medicine

Abstract

Neurodegenerative diseases (NDs) have traditionally been viewed as disorders driven by individual pathological processes, including protein aggregation, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, impaired autophagy, and neuroinflammation. However, growing evidence demonstrates that these mechanisms are not isolated events but interconnected manifestations of disrupted intracellular organelle communication. Dynamic interactions among mitochondria, the ER, lysosomes, peroxisomes, and other organelles coordinate calcium signaling, bioenergetics, proteostasis, lipid metabolism, and cellular stress adaptation, thereby preserving neuronal homeostasis. Progressive disruption of this communication network represents a fundamental driver of neuronal dysfunction and degeneration, suggesting that restoration of organelle homeostasis may constitute a more effective therapeutic strategy than targeting individual molecular pathways. In parallel, regenerative medicine has evolved beyond the concept of cell replacement toward approaches that enhance the resilience and repair capacity of surviving cells. Among these, mesenchymal stem cell (MSC)-derived secretomes and extracellular vesicles (EVs) have emerged as promising cell-free therapeutics owing to their diverse repertoire of proteins, lipids, metabolites, cytokines, growth factors, and regulatory RNAs capable of simultaneously modulating multiple cellular pathways. Accumulating evidence indicates that these bioactive cargos modulate mitochondrial function, alleviate ER stress, improve autophagy-lysosomal activity, reduce oxidative stress and neuroinflammation, and reinforce proteostasis, collectively promoting intracellular homeostasis. Here, we propose organelle homeostasis as a promising focus for regenerative medicine and discuss how cell-free therapies may redefine therapeutic strategies for NDs by restoring the intracellular communication networks that sustain cellular resilience. Finally, we highlight current translational challenges and future opportunities for engineering next-generation cell-free therapeutics targeting complex diseases.