A Glutathione-Responsive Prodrug Nanosystem for Colorectal Cancer: Synergistic Co-Delivery of Paclitaxel and Curcumin to Combat Multidrug Resistance and Reinvent the Immunosuppressive Microenvironment.

The management of colorectal cancer is constrained by a self-perpetuating vicious cycle, driven initially by gut microbiota dysbiosis that triggers chronic inflammation, which in turn promotes the establishment of an immunosuppressive tumor microenvironment and multidrug resistance. We engineered a glutathione (GSH)-responsive prodrug micellar nanosystem (PSC/PTX) for the synergistic co-delivery of paclitaxel (PTX) and curcumin (CUR). In this nanoplatform, CUR was covalently conjugated to form a prodrug via disulfide linkages, while PTX was physically encapsulated within the micelles, ensuring the precise release of the 2 drugs in the tumor-specific microenvironment. The nanoplatform reverses P-glycoprotein-mediated drug efflux, prolongs the circulation time, improves the bioavailability, and enhances the accumulation at tumor sites of 2 drugs. This nanoplatform exerts multifaceted therapeutic efficacy. Initially, it reinstates the balance of intestinal microbiota by increasing the abundances of beneficial microorganisms (e.g., Bacteroidetes, Eubacterium, and Bifidobacterium) while decreasing those of harmful bacteria (e.g., Bacteroides fragilis and Escherichia coli). Additionally, it inhibits pro-tumor inflammatory factors by attenuating the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), ultimately leading to a remodeling of the immunosuppressive tumor microenvironment (TME). This process involves boosting the infiltration of cytotoxic CD8+ T cells, decreasing the number of immunosuppressive regulatory T cells (Tregs), and repolarizing macrophages to the M1 phenotype (CD86+↑, CD206+↓). Collectively, this integrated and coordinated strategy breaks the self-sustaining vicious cycle of microbiota-driven, inflammation-fueled carcinogenesis and multidrug resistance via the synergistic modulation of chemotherapy sensitization, immunity, and the microbiota, thereby offering a novel and promising therapeutic modality for refractory colorectal cancer.