Biocompatible Polymer-Modified Nanoplatform for Ferroptosis-Enhanced Combination Cancer Therapy

Ferroptosis is a novel type of iron-dependent non-apoptotic pathway that regulates cell death and shows unique mechanisms including causing lipid peroxide accumulation, sensitizing drug-resistant cancers, priming immunity by immunogenic cell death, and cooperatively acting with other anticancer modalities for eradicating aggressive malignancies and tumor relapse. Recently, there has been a great deal of effort to design and develop anticancer biocompatible polymeric nanoplatforms including polypeptide and PEGylated ones to achieve effective ferroptosis therapy (FT) and synergistic combination therapies including chemotherapy (CT), photodynamic therapy (PDT), sonodynamic therapy (SDT), photothermal therapy (PTT), gas therapy (GT) including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂ S), and immunotherapy (IT). To be noted, the combo therapies such as FT-CT, FT-PTT, FT-GT, and FT-IT are attracting much efforts to fight against intractable and metastatic tumors as they can generate synergistic antitumor effects and immunogenic cell death (ICD) effects or modulate immunosuppressive tumor microenvironments to initiate strong antitumor immunity and memory effects. The polymeric Fenton nano-agents with good biosafety and high anticancer efficacy will provide a guarantee for their applications. In this review, various biocompatible polymer-modified nanoplatforms designed for FT and combo treatments are summarized for anticancer therapies and discussed for potential clinical transitions.