Colon-specific controlled release of oral liposomes for enhanced chemo-immunotherapy against colorectal cancer

A colon-specific drug delivery system has great potential for the oral administration of colorectal cancer. However, the uncontrollable <i>in vivo</i> fate of liposomes makes their effectiveness for colonic location, and intratumoral accumulation remains unsatisfactory. Here, an oral colon-specific drug delivery system (CBS-CS@Lipo/Oxp/MTZ) was constructed by covalently conjugating <i>Clostridium butyricum</i> spores (CBS) with drugs loaded chitosan (CS)-coated liposomes, where the model chemotherapy drug oxaliplatin (Oxp) and anti-anaerobic bacteria agent metronidazole (MTZ) were loaded. Following oral administration, CBS germinated into <i>Clostridium butyricum</i> (CB) and colonized in the colon. Combined with colonic specifically <i>β</i>-glucosidase responsive degrading of CS, dual colon-specific release of liposomes was achieved. And the accumulation of liposomes at the CRC site furtherly increased by 2.68-fold. Simultaneously, the released liposomes penetrated deep tumor tissue <i>via</i> the permeation enhancement effect of CS to kill localized intratumoral bacteria. Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB, the intratumoral pathogenic bacteria were eliminated fundamentally, blocking their recruitment to immunosuppressive cells. Furtherly, synchronized with lipopolysaccharide (LPS) released from MTZ-induced dead <i>Fusobacterium nucleatum</i> and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells, they jointly enhanced tumor infiltration of CD8⁺ T cells and reactivated robust antitumor immunity.