Shefang Ye

Iron-dependent accumulation of reactive oxygen species (ROS) and lipid peroxidation play key roles in ferroptosis, which has been an attractive strategy to kill tumor cells. However, the rapid annihilation of hydroxyl radicals (˙OH) produced from the Fenton reaction has become a major obstacle in inducing lipid peroxidation in cells. In this study, we develop a nano-delivery system of unsaturated phospholipid (Lip) and polyacrylic acid (PAA) functionalized FeOCl nanosheets (FeOCl@PAA-Lip). In this system, the ˙OH radicals produced from the Fenton reaction between FeOCl nanosheets and endogenous H₂O₂ of tumor cells attack Lip on the nanosheets in situ to initiate the lipid peroxidation chain reaction, which not only realizes free radical conversion but also leads to the amplification of ROS and lipid peroxides, thus enhancing tumor ferroptosis. The in vitro and in vivo results confirmed that FeOCl@PAA-Lip nanosheets exhibited specific tumor cell-killing effects, good biocompatibility, long circulation time, low side effects, high tumor targeting and an excellent tumor inhibition rate (73%). The Lip functionalization strategy offers a paradigm of enhancing ferroptosis treatment by conversion of ˙OH/phospholipid radicals/lipid peroxyl radicals and strengthening lipid peroxidation.

The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic antitumor therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of metal coordination-based nanomedicines, we proposed an effective strategy for synergistic cancer treatment in response to the special tumor microenvironmental properties. Herein, we present novel metal-coordinated multifunctional nanoparticles (NPs) by the Cu²⁺-triggered assembly of photosensitizer indocyanine green (ICG) and hypoxia-activated anticancer prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within tumor sites via the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSH elimination, and Cu⁺-mediated ^•OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic tumor therapy. Both in vitro and in vivo evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced tumor treatment.

Tumor cells are rich in antigens, which provide a reliable antigen library for the design of personalized vaccines. However, an effective tumor vaccine vector that can efficiently deliver antigens to lymphoid organs to stimulate strong CD8⁺ cytotoxic T-lymphocyte immune response is still lacking. Here we designed a dual-antigen delivery system based on hepatitis B virus core antigen virus-like particles (HBc VLPs). We first confirmed that different antigen-loaded HBc VLP monomers could be assembled into nanoparticles (hybrid VLPs). Hybrid VLPs could slightly enhance bone marrow-derived dendritic cell maturation in vitro. Strikingly, hybrid VLPs could generate antigen-specific antitumor immunity and innate immunity in vivo which could significantly inhibit tumor growth or metastatic formation in a subcutaneous tumor or lung metastatic tumor model, respectively. Moreover, dual-epitope vaccination generated enhanced T-cell responses that potently inhibited tumor growth and metastatic formation. Together, this study provides a new powerful concept for cancer immunotherapy and suggests a novel design for VLP-based personalized nanomedicine.

A rapid molecular diagnostic technique targeting circulating tumor DNA (ctDNA) has become one of the most clinically significant liquid biopsy methods for non-invasive and timely diagnosis of cancer.