Oral epimedium nanovesicles promote hematopoietic stem cell regeneration via gut-microbiota-bone marrow axis to mitigate chemotherapy-induced myelosuppression

Research Background：

Myelosuppression constitutes a prevalent and dose-limiting complication of cancer chemotherapy. Current standard interventions primarily target committed hematopoietic progenitors rather than hematopoietic stem cells (HSCs), frequently resulting in the exhaustion of hematopoietic reserves. Additional limitations—including substantial treatment costs and requirements for parenteral administration—render these approaches unsuitable for prophylactic or long-term management. There is consequently an urgent clinical need to develop safer, more sustainable, and cost-effective therapeutic alternatives.

In exploring potential anti-myelosuppressive strategies, the team focused on the traditional Chinese herb Epimedium, which contains multiple hematopoiesis-promoting constituents and demonstrates immunomodulatory and pro-hematopoietic properties. The Epimedium-based formulation "Shengbai Mixture" has been clinically utilized for myelosuppression management, offering distinct advantages over conventional therapies through its oral administration route, favorable cost-effectiveness, and formulation stability.

Subsequent investigation revealed that orally administered herbal medicines can exert therapeutic effects through gut microbiota modulation. Emerging evidence indicates that the gut microbiota can directly regulate bone marrow hematopoiesis through specific targeting mechanisms. Notably, Epimedium itself demonstrates capacity to reshape hematopoietic-associated microbial communities, suggesting a potential mechanism for promoting HSC expansion.

However, conventional Epimedium extracts face pharmacological challenges including poor solubility and limited oral bioavailability. Among innovative delivery strategies, exosomes have emerged as a promising platform for herbal medicine administration, offering advantages such as facile preparation, high yield, excellent biocompatibility, and enhanced bioavailability. Orally delivered plant-derived exosomes can enhance intestinal mucosal absorption efficiency, improve drug bioavailability, and treat diseases through gut microbiota regulation.

Based on this collective evidence, the research team developed orally administrable Epimedium Nanovesicles (ENVs) to overcome the pharmacokinetic limitations of traditional extracts. Furthermore, this innovative approach is expected to modulate the gut microbiota, promote HSCs proliferation, and alleviate myelosuppression without inducing hematopoietic reserve depletion—addressing key limitations of current therapeutic strategies.

Research Progress:

The team first isolated ENVs from Epimedium leaves and characterized their morphology and cargo. These ENVs were identified as spherical particles approximately 50–100 nm in diameter with high stability. Compositional analysis revealed that they are enriched with bioactive compounds (e.g., icariin), lipids (e.g., ceramide), and metabolites associated with hematopoietic promotion and microbiota modulation. Using simulated gastrointestinal fluids and in vivo imaging, The team demonstrated that ENVs maintain structural integrity after oral administration and exhibit prolonged retention within the digestive tract.

To evaluate the therapeutic potential of ENVs, a mouse model of myelosuppression was established using cyclophosphamide (CTX). Oral administration of ENVs significantly alleviated bone marrow suppression by modulating hematopoiesis, gut microbiota composition, lactate metabolism, and the bone marrow niche. Mechanistic studies revealed that ENVs restored the gut microbial community in myelosuppressed mice, elevated levels of microbially derived short-chain fatty acids (SCFAs), and promoted the proliferation of Lactobacillus, leading to increased lactate production. This cascade ultimately activated the “gut–lactate–bone marrow” axis.

Further analyses indicated that ENVs restored the population of LepR⁺ mesenchymal stem cells (MSCs) secreting stem cell factor (SCF) in the bone marrow, elevated local concentrations of SCF and stromal cell-derived factor-1 (SDF-1), and rejuvenated the hematopoietic microenvironment, thereby promoting the proliferation of hematopoietic stem cells. Collectively, these effects contributed to the amelioration of myelosuppression. Additionally, oral administration of ENVs in healthy mice confirmed their biocompatibility and safety profile.

Future Perspectives：
This study demonstrates that ENVs derived from the traditional medicinal herb Epimedium promote HSCs proliferation and restore bone marrow function through a "gut–lactate–bone marrow" axis. These findings provide a robust theoretical and experimental foundation for applying traditional Chinese medicine in hematopoietic recovery. As a safe and broadly applicable therapeutic strategy, ENVs hold significant clinical translation potential, offering a safer, more durable, and cost-effective treatment option for chemotherapy-treated cancer patients.

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.