A TME-responsive polysaccharide nanoplatform integrating synergetic therapy for cancer

A self-assembling nanoplatform based on FOB (a heteropolysaccharide from Fomitopsis officinalis) named QU@FOB-FcDBA was developed in this study. A dynamic boronate ester bond, a pH-sensitive covalent linkage formed through reversible dehydration reactions, linked FOB and 1,1'-ferrocenediboronic acid (FcDBA) while encapsulating the hydrophobic drug quercetin (QU). The formulation not only enhanced the water solubility of QU, but also indirectly improved the clinical utilization rate of QU. QU@FOB-FcDBA exhibited unique dual pH/ROS-responsive characteristics, enabling precise recognition and selective response to the acidic microenvironment and elevated reactive oxygen species (ROS) levels in tumor tissues. This ensured the accurate and controlled release of QU and FcDBA, achieving synergistic deep penetration and enhanced therapeutic efficacy through the combined induction of ferroptosis and chemotherapy. In vivo, QU@FOB-FcDBA effectively suppressed tumor progression and metastasis. Mechanistically, it induced cell death via multiple pathways: triggering ferroptosis through ROS accumulation, lipid peroxidation (LPO), and glutathione (GSH) depletion, as well as inducing apoptosis. In vitro, FOB upregulated macrophage surface markers (CD40, CD80, CD86, MHC-II) and nitric oxide (NO) expression. This innate immune activation may directly contribute to antitumor effects and establish a favorable immune microenvironment for immunotherapy. These results position QU@FOB-FcDBA as a promising platform integrating ferroptosis induction and chemotherapy for improved cancer treatment.