Milk exosomes delivery of KPT-330 alleviates gastrointestinal adverse reactions and provides effective anti-diffuse large B-cell lymphoma therapy.

The FDA granted accelerated approval to KPT-330 (selinexor) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, 80% of patients experienced gastrointestinal toxicity. Milk exosomes (mExos) possess high stability in the gastrointestinal environment and the ability to traverse the gastrointestinal barrier, making them an excellent choice for oral drug delivery. Here, we isolated and identified mExos, which demonstrated good stability in simulated fed-state gastrointestinal fluids. These exosomes effectively encapsulated KPT-330, enhancing drug accessibility within DLBCL and sustaining intracellular accumulation over an extended period. mExo-KPT-330 showed a slight increase in size, with no apparent changes in shape or biological characteristics. mExo-KPT-330 outperformed free KPT-330 in vitro, exhibiting a more potent DLBCL-suppressive effect. Furthermore, in DLBCL mouse models, mExo-KPT-330 exhibited a significantly reduced disease burden compared to free KPT-330. Notably, mExo-KPT-330 alleviated the disorganization of the intestinal epithelium, edema in the villous stroma of the small intestine, lymphocyte infiltration, and elevated serum levels of LPS and IL-12 caused by free KPT-330 treatment. Additionally, mExo-KPT-330 exhibited no organ toxicity. Encapsulating KPT-330 in mExos significantly increased its permeability across the intestinal epithelial barrier. Moreover, mExo-KPT-330 maintained its intact exosomal form after being transported across the intestinal epithelial barrier. Collectively, our results suggest that mExo loaded with KPT-330 has promising anti-DLBCL effects and that oral administration is beneficial for alleviating gastrointestinal adverse reactions induced by KPT-330.