Dual-targeted exosome nanoplatform co-delivering doxorubicin and Fuzi Lizhong Tang bioactives for synergistic DLBCL therapy and chemotherapy-induced diarrhea management.

The management of chemotherapy-induced diarrhea (CID) in diffuse large B-cell lymphoma (DLBCL) requires strategies that concurrently address intestinal protection and tumor-targeted therapy. In this study, we developed a multifunctional nano-delivery system based on natural exosomes to co-encapsulate doxorubicin (DOX) and bioactive components derived from the traditional Chinese medicine Fuzi Lizhong Tang (gingerol and atractylenolide), aiming to synchronize DLBCL-targeted chemotherapy with CID alleviation. Exosomes (TEX) isolated from the human DLBCL cell line OCI-Ly3 were loaded with DOX and the herbal components via electroporation, yielding TEX@DOX-Herb. The tumor-homing capability, mediated by surface CD19/CD20 proteins, enabled precise DOX delivery, resulting in superior tumor growth inhibition (∼90 % vs. ∼70 % for DOX alone) and significantly prolonged survival (overall survival: 38 days vs. 30 days with DOX alone) in xenograft models. Concurrently, the exosomes exhibited intestinal tropism, facilitating the localized release of gingerol and atractylenolide. This led to a marked reduction in severe diarrhea incidence (∼40 %) and restored intestinal barrier integrity, as evidenced by suppressed NF-κB-driven inflammation and upregulated tight junction proteins. Furthermore, TEX@DOX-Herb showed negligible systemic toxicity. These findings highlight the dual-targeting potential of tumor-derived exosomes as a biocompatible platform to synergize traditional herbal medicine with modern chemotherapy, offering a promising therapeutic paradigm for DLBCL patients to mitigate chemotherapy complications while optimizing oncologic outcomes.