Targeted Elimination of the Oral Pathogen to Overcome Chemoresistance of Oral Squamous Cell Carcinoma by Biologically Derived Nanotherapeutics

Local oral microbiota are closely related to the tumorigenesis and therapeutic response of oral cancer. In this study, we have validated that oral commensal <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) is highly responsible for chemoresistance and contributes to the poor therapeutic outcome of traditional chemotherapy. Accordingly, the biologically derived nanovesicles from ginger (GDNVs) with excellent <i>P. gingivalis</i> elimination ability are explored to transport the clinically used drug paclitaxel (PTX) for potentiating the therapeutic efficiency. Taking advantage of active targeting and inhibition abilities of GDNVs against <i>P. gingivalis</i>, the PTX-loaded GDNVs nanosystem (P-GDNVs) can enrich in the <i>P. gingivalis</i>-colonized tumor tissues and effectively inhibit the growth of <i>P. gingivalis</i> for downregulating the IL-6/pSTAT3/P-gp pathway, thereby reducing the efflux of intracellular drugs to overcome chemoresistance. By evaluating both <i>P. gingivalis</i>-infected tumor cells and <i>P. gingivalis</i>-infiltrated tumor-bearing mice, P-GDNVs show a much enhanced tumor cell killing effect, as compared with free PTX. This naturally occurring nanotherapeutic system represents an effective bioactive material for targeted elimination of host microbiota to boost therapeutic response, showing great promise to combat commensal microbiota-rich tumors.