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.