Ferumoxytol promotes hematopoietic stem cell post-injury regeneration as a ROS scavenger

Under stress conditions such as ex vivo culture, chemotherapy, irradiation and infection, hematopoietic stem cells (HSCs) actively divide to maintain blood cell production, during which reactive oxygen species (ROS) produces and accumulates, and eventually causes HSC exhaustion and hematopoietic failure. However, it remains largely elusive how to relieve ROS in stressed HSCs and facilitate the hematopoietic post-injury regeneration. Here, we report that ferumoxytol (Feraheme, FMT), an FDA-approved nanodrug, is a powerful ROS scavenger and could recover the functions of stress HSCs. Due to lower levels of TFEB expression and lysosomal activity in HSCs as compared to leukemia cells, FMT is less degraded and more distributed in the cytoplasm. Under ex vivo culture, chemotherapy and irradiation conditions, FMT effectively mitigates ROS and apoptosis in stressed HSCs and promotes hematopoietic post-injury regeneration. Mechanistically, the catalase (CAT)-like activity of FMT reduces intracellular levels of H₂O₂ and diminishes H₂O₂-induced DNA damage and cytotoxicity. Finally, FMT maintains long-term regenerative capacity of transplanted HSCs in pre-conditioned leukemic mice, and has an excellent biosafety profile. Collectively, our study deciphers the role of nanozymes in hematopoietic regeneration and highlights the potential clinical applications of FMT in promoting the stress-induced hematopoietic recovery.