5‐Fluorouracil Loaded Prebiotic–Probiotic Liposomes Modulating Gut Microbiota for Improving Colorectal Cancer Chemotherapy

Abstract The gut microbiota exerts inhibitory effects on the occurrence and progression of colorectal cancer (CRC) through various mechanisms. Compared to traditional microbiota regulation methods, prebiotics and probiotics demonstrate significant advantages in terms of safety and patient adaptability. Their synergy not only improves the intestinal environment but also enhances the host's anti‐tumor immune response. 5‐Fluorouracil (5‐FU) is a first‐line chemotherapy drug that has a short half‐life and low bioavailability. However, if administered in an untargeted manner, 5‐FU also causes adverse reactions. Liposomes can improve the pharmacokinetic profile of drugs and provide targeted delivery to the tumor site, thereby reducing side effects. In this work, a 5‐FU‐loaded liposome is modified with the prebiotic xylan derivative Sxy and the probiotic Akkermansia muciniphila active phospholipid homolog 1,2‐dipalmitoylphosphatidy‐lethanolamine (DPPE) to construct FLSK. The latter effectively prolongs the intestinal transport and release of 5‐FU, maintaining high drug concentrations at the tumor site. FLSK is found to inhibit tumor growth and significantly extends the survival period of mice. In addition, FLSK promotes anti‐tumor immunity and regulation of the gut microbiota. Combining the merits of prebiotics and probiotics, FLSK provides a potential strategy for integrating chemotherapy with gut microbiota regulation therapy for the treatment of CRC.