Oral <i>Epimedium</i> nanovesicles promote hematopoietic stem cell regeneration via gut-microbiota-bone marrow axis to mitigate chemotherapy-induced myelosuppression

Myelosuppression is a common and severe side effect of cancer chemotherapy, with current treatments hindered by limitations such as depletion of hematopoietic reserves, poor patient compliance, delayed therapeutic onset, and high cost. To overcome these challenges, we developed Epimedium-derived nanovesicles (ENVs) from the traditional Chinese medicinal herb <em>Epimedium</em>, addressing the solubility and bioavailability issues associated with conventional extracts. ENVs encapsulate bioactive constituents, including icariin and hematopoiesis-promoting ceramides. In a cyclophosphamide (CTX)-induced myelosuppression mouse model, prophylactic and therapeutic oral administration of ENVs effectively alleviated hematopoietic suppression, significantly outperforming the <em>Epimedium</em>-based herbal extract “Joungal” (Shengbai Formula) despite equivalent icariin content. Notably, ENVs promoted hematopoietic stem cell (HSC) proliferation—an outcome rarely achieved with existing therapies. Mechanistically, ENVs modulated the gut microbiota, enriching <em>Lactobacillus</em> species and enhancing lactate production. This microbiota-driven lactate signaling stimulated LepR⁺ mesenchymal stem cells (MSCs) in the bone marrow niche to secrete stromal cell-derived factor-1 (SDF-1) and stem cell factor (SCF), thereby supporting HSC expansion and restoring hematopoietic function. <em>In vivo </em>safety evaluations confirmed the excellent biocompatibility of ENVs. Our findings uncover a gut–lactate–bone marrow axis through which ENVs enhance hematopoiesis and promote HSC regeneration. This work introduces a cost-effective, scalable, and orally administrable biomaterial platform with strong translational potential for the prevention and treatment of chemotherapy-induced myelosuppression.