Supramolecular Self-Assemblies with Self-Supplying H₂O₂ and Self-Consuming GSH Property for Amplified Chemodynamic Therapy

Fe-based chemodynamic therapy (CDT) has become one potential method for cancer therapy due to its lower side effect and tumor-specific property. During the process of CDT, the lack of active targeting and biodegradable ability, insufficient endogenous H2O2, and overexpressed GSH in the tumor were responsible for the unsatisfactory therapeutic performance. Hence, we report host–guest interaction-based supramolecular polymers (HGSPs) that were constructed with the biomacromolecule β-cyclodextrin-grafted hyaluronic acid (HA-CD) as the active targeting host unit and hydrophobic ROS-responsive ferrocene-(phenylboronic acid pinacol ester) (Fc-BE) as the guest unit. HGSPs can further self-assemble into self-assemblies (HGSAs) and encapsulate PA as the prooxidant. After CD44-receptor-mediated cellular internalization, HGSAs could disassemble and release PA to elevate the H2O2 level for the production of higher cytotoxic hydroxyl radicals (•OH) through the Fc-induced Fenton reaction. Moreover, quinone methide (QM) was generated to downregulate antioxidant GSH. The enhancement of H2O2 and consumption of GSH were favorable for CDT due to the amplified oxidative stress. In vivo experimental results indicated that HGSAs@PA might be used as an active targeting amplified CDT agent.