Natural Flavonoid and Fungal Polysaccharide-Based Redox-Responsive Nanogels for Synergistic Tumor Chemo-Immunotherapy

Cancer remains a leading cause of global mortality, underscoring the urgent need for safe, effective, and innovative therapeutic strategies. Nanotechnology, particularly nanogels, offers promising opportunities for cancer treatment. Natural flavonoids exhibit significant antitumor activity, but their poor water solubility and low bioavailability limit clinical application. Natural polysaccharides overcome these challenges through excellent biocompatibility, biological activity, and potential as nanomaterial scaffolds. Herein, a glutathione (GSH)-responsive disulfide bond cross-linker, DBHD, was successfully synthesized. Using DBHD, a redox-responsive nanogel system (QFD NGs) was constructed through covalent cross-linking of the natural macromolecule <i>Fomitopsis officinalis</i> polysaccharide (FOBP) and encapsulation of quercetin (QU). <i>In vitro</i> release assays demonstrated that QFD NGs rapidly released drugs under high GSH concentrations characteristic of the tumor microenvironment. Cell culture and zebrafish model experiments confirmed that QFD NGs efficiently inhibited tumor cell proliferation, invasion, and metastasis while inducing apoptosis. Additionally, QFD NGs demonstrated remarkable immunomodulatory activity by activating macrophages, promoting nitric oxide (NO) production, and upregulating costimulatory molecules (CD40, CD80, CD86), as well as MHC-II expression. This study introduces QFD NGs as a synergistic therapeutic platform combining chemotherapy and immunotherapy, offering a promising strategy for developing efficient, low-toxicity cancer treatments based on natural products.