Boosting the synergism between cancer ferroptosis and immunotherapy via targeted stimuli-responsive liposomes.

Both ferroptotic therapy and immunotherapy have been widely employed in cancer treatment. However, ferroptotic cell death fails to induce dendritic cells maturation, which limits the therapeutic outcome of ferroptotic cancer therapy. To address this, the current work reports a tailored liposome to establish a positive loop between ferroptotic therapy and immunotherapy. As the key component of liposome, a unique phospholipid is designed to bear two arachidonic acid tails. The liposome is further surface-engineered with fucose ligand and physically encapsulates immunostimulatory CpG oligodeoxynucleotides (ODNs). The tailored liposome shows enhanced cellular uptake in a model 4T1 cell line. Meanwhile, the high level of reactive oxygen species in cancer cells can induce ferroptosis-specific peroxidation of DAPC and trigger the release CpG ODNs. The CpG ODNs further enable the maturation of dendritic cells and enhance the effector function of CD8+ T cells. IFN-γ released from CD8+ T cells promotes cancer cell ferroptosis via inhibiting SLC7A11 and suppressing the biosynthesis of glutathione. The tailored liposome can also act in synergism with PD-L1 antibody, resulting in enhanced anti-cancer efficacy in a 4T1 tumor-bearing mice model. This work provides a promising strategy for cancer treatment through orchestrating ferroptotic therapy and immunotherapy.

Chondroitin sulfate modified calcium phosphate nanoparticles for efficient transfection via caveolin-mediated endocytosis.

Efficient transfection remains a challenge for gene delivery in both cell biological scientific research and gene therapeutic fields. Existing transfection strategies rarely pay attention to altering the endocytosis pathway of nanocarriers for transfection efficiency improvement. In this work, we innovatively postulated that calcium phosphate nanoparticles coated with glycosaminoglycan could be internalized by cells mainly through caveolin-mediated endocytosis pathway allowing genes to bypass lysosome route, and hence enhance the transfection efficiency. To achieve this, we developed calcium phosphate nanoparticles (CP-ALN-CS) coated with chondroitin sulfate (CS) and alendronate (ALN) in a modular manner. The CP-ALN-CS had a hydrodynamic size of 131.0 ± 8.7 nm and exhibited favorable dispersity, stability, and resistance to nuclease degradation. Unlike conventional calcium phosphate and PEI-based transfection, CP-ALN-CS exhibited efficient cellular uptake with co-localization in Golgi apparatus and endoplasmic reticulum. Through bypassing the lysosome involved cellular uptake route, CP-ALN-CS can effectively protect genes from degradation and relieve cytotoxicity. After loading plasmid DNA, CP-ALN-CS showed extraordinary transfection efficiency in HEK 293T cells, outperforming the PEI which is considered as the gold standard. The current work provides a novel and facile approach to improve gene transfection efficiency and is valuable for the design of next-generation in vitro transfection reagents.

Coumarin-Based Fluorescent Inhibitors for Photocontrollable Bioactivation.

Activation of the IRE-1/XBP-1 pathway is related to many human diseases. Coumarin-based derivatives acting as both IRE-1 inhibitors and bright fluorophores are highly desirable to establish an integrated fluorescent inhibitor system. Here, we take insights into the aqueous stability of a photocaged IRE-1 inhibitor PC-D-F07 through a structure activity relationship. The substituent effects indicate that the electron-withdrawing -NO2 moiety in the photocage combined with the tricyclic coumarin fluorophore contribute to the structural stability of PC-D-F07. To optimize the photocage of PC-D-F07, we incorporate a 1-ethyl-2-nitrobenzyl or 2-nitrobenzyl photolabile moiety on the hydroxyl group of the IRE-1 inhibitor to generate RF-7 and RF-8. Upon photoactivation, both RF-7 and RF-8 present an increased fluorescence response, sequentially enabling the unlocking of the ortho-1,3-dioxane acetal for the release of active IRE-1 inhibitors. Moreover, RF-7 exhibits a high repolarization ratio of converting M2-type tumor-associated macrophages (M2-TAMs) to M1-type immune-responsive macrophages. This provides a novel prodrug strategy of modulating druggable fluorophore backbones to achieve spatiotemporally controllable drug release for precise cancer treatment.