β-glucan nanotubes improve oral doxorubicin delivery for colorectal cancer by microbiota-mediated colon targeting and reduced toxicity.

Traditional chemotherapy against colorectal cancer (CRC) is limited by systemic toxicity and side effects, highlighting the need for safe and effective drug delivery systems. In this study, β-glucan self-assembled nanotubes (β-gluSNTs) were developed as colon-targeted delivery platforms, which enable microbiota-triggered drug release in the colon. By encapsulating the typical chemotherapeutic agent doxorubicin (DOX) within these nanotubes, the obtained β-gluSNTs-DOX complex was oral administrated to against CRC in an orthotopic mouse model, with a tumor suppression rate reaching 42.55 ± 0.18 %. β-gluSNTs-DOX exhibited high drug-loading capacity (30.5 ± 0.16 %) and protected DOX from premature release in the upper gastrointestinal tract, resulting in enhanced drug accumulation at the colonic tumor site. Notably, due to encapsulation of DOX inside the β-gluSNTs, the β-glucan shell helps alleviate oral DOX-induced systemic toxicity, inflammation, and gut microbiota dysbiosis, while promoting M1 macrophage polarization and antitumor immunity, thereby synergistically enhancing the oral therapeutic efficacy of DOX. In summary, these findings suggest that β-glucan-based nanotubes represent a promising, low-toxicity, colon-targeted delivery system for CRC therapy with additional benefits in regulating the gut microbiota and tumor immune microenvironment.