Near infrared II excitation conjugated polymers-based phototheranostic nanoplatform for hyperthermia-enhanced ferroptosis and immunotherapy

Ferroptosis has the potential to induce immunogenic cell death (ICD) and remodel the immunosuppressive tumor microenvironment (TME). However, intracellular antioxidant glutathione (GSH) inhibits the efficacy of ferroptosis. Consequently, enhancing iron ion uptake while simultaneously depleting GSH presents a promising strategy to improve ferroptosis efficacy. Herein, we have developed phenylboronic acid-modified near infrared II photothermal therapy (NIR-II PTT) conjugated polymers DPP-CPDT-PBA (DCP), which co-load Fe²⁺ and GSH scavenger cisplatin (Pt), and encapsulate them within an amphiphilic DSPE-mPEG₂₀₀₀ to finally construct nanoplatform DCP@Pt@Fe. The formulated DCP@Pt@Fe exhibits outstanding NIR-II photothermal property and NIR-II imaging tracking capability. The thermo- and acidic TME-responsive release of Pt and Fe²⁺ synergistically induces ferroptosis in cancer cells through Pt-mediated GSH consumption by forming stable Pt-GSH complexes and Fe²⁺-driven reactive oxygen species (ROS) generation <i>via</i> NIR-II PTT-enhanced Fenton reactions. Notably, ferroptotic tumor cells exhibit high immunogenicity, reprogram tumor-associated macrophage polarization, promote dendritic cell maturation, mobilize T cell activation, and significantly reverse the immunosuppressive TME. Simultaneously, interferon-γ (IFN-γ) produced by tumor-infiltrating immune cells inhibits SLC7A11 expression in cancer cells, which contributes to the ferroptosis therapeutic efficacy. Consequently, our nanoplatform DCP@Pt@Fe effectively eradicates ovarian cancer <i>via</i> synergistic NIR-II-PTT/ferroptosis/immunotherapy, providing an exciting new avenue for therapeutic interventions.