An emerging antibacterial nanovaccine for enhanced chemotherapy by selectively eliminating tumor-colonizing bacteria.

Fusobacterium nucleatum (F. nucleatum), an oral anaerobe, is prevalent in colorectal cancer and is closely related to increased cancer cell growth, metastasis, and poor treatment outcomes. Bacterial vaccines capable of selectively eliminating bacteria present a promising approach to targeting intratumor F. nucleatum, thereby enhancing cancer treatment. Although adjuvants have been employed to enhance the immune response, the vaccine's effectiveness is constrained by inadequate T-cell activation necessary for eradicating intracellular pathogens. In this study, we developed a minimalistic, biomimetic nanovaccine by integrating highly immunostimulatory adjuvant cholesterol-modified CpG oligonucleotides into the autologously derived F. nucleatum membranes. Compared to the traditional vaccines consisting of inactivated bacteria and Alum adjuvant, the nanovaccine coupled with bacterial membranes and adjuvants could remarkably improve multiple antigens and adjuvant co-delivery to dendritic cells, maximizing their ability to achieve effective antigen presentation and strong downstream immune progress. Notably, the nanovaccine exhibits outstanding selective prophylactic and therapeutic effects, eliminating F. nucleatum without affecting intratumoral and gut microbiota. It significantly enhances chemotherapy efficacy and reduces cancer metastasis in F. nucleatum-infected colorectal cancer. Overall, this work represents the rational application of bacterial nanovaccine and provides a blueprint for future development in enhancing the antitumor effect against bacterial-infected cancer.

Delivery of short chain fatty acid butyrate to overcome Fusobacterium nucleatum-induced chemoresistance.

The gut microbiota is closely associated with the progression of colorectal cancer (CRC) in which Fusobacterium nucleatum (F. nucleatum) was found to induce cancer resistance to chemotherapeutics. To relieve F. nucleatum-induced drug resistance, herein, we found that short-chain fatty acid butyrate can inhibit the growth, enrichment and adhesion of F. nucleatum in colorectal cancer tissues by downregulating the expression of adhesion-associated outer membrane proteins, including RadD, FomA, and FadA, to reduce the colonization and invasion of F. nucleatum and relieve the chemoresistance induced by F. nucleatum. Leveraging the killing effect of butyrate on F. nucleatum, sodium butyrate (NaBu) was encapsulated in liposomes or prepared as NaBu tablets with Eudragit S100 coating and administered by intravenous injection or oral administration, respectively. Interestingly, both intravenous administration of NaBu liposomes and oral delivery of NaBu tablets could effectively inhibit the proliferation of F. nucleatum and significantly improve the therapeutic efficacy of oxaliplatin in mice with subcutaneous colorectal tumors, orthotopic colorectal tumors and even spontaneously formed colorectal tumors. Thus, our work provides a simple but effective formulation of NaBu to relieve F. nucleatum-induced chemoresistance, exhibiting ideal clinical application prospects.