Sequential Ubiquitination and Phosphorylation Epigenetics Reshaping by MG132-Loaded Fe-MOF Disarms Treatment Resistance to Repulse Metastatic Colorectal Cancer.

Abnormal epigenetic regulation is identified to correlate with cancer progression and renders tumor refractory and resistant to reactive oxygen species (ROS)-based anti-tumor actions. To address it, a sequential ubiquitination and phosphorylation epigenetics modulation strategy is developed and exemplified by the well-established Fe-metal-organic framework (Fe-MOF)-based chemodynamic therapy (CDT) nanoplatforms that load the 26S proteasome inhibitor (i.e., MG132). The encapsulated MG132 can blockade 26S proteasome, terminate ubiquitination, and further inhibit transcription factor phosphorylation (e.g., NF-κB p65), which can boost pro-apoptotic or misfolded protein accumulations, disrupt tumor homeostasis, and down-regulate driving genes expression of metastatic colorectal cancer (mCRC). Contributed by them, Fe-MOF-unlocked CDT is magnified to considerably elevate ROS content for repulsing mCRC, especially after combining with macrophage membrane coating-enabled tropism accumulation. Systematic experiments reveal the mechanism and signaling pathway of such a sequential ubiquitination and phosphorylation epigenetics modulation and explain how it could blockade ubiquitination and phosphorylation to liberate the therapy resistance to ROS and activate NF-κB-related acute immune responses. This unprecedented sequential epigenetics modulation lays a solid foundation to magnify oxidative stress and can serve as a general method to enhance other ROS-based anti-tumor methods.

Extracellular Matrix Viscosity Reprogramming by In Situ Au Bioreactor-Boosted Microwavegenetics Disables Tumor Escape in CAR-T Immunotherapy.

Incomplete microwave ablation (iMWA) caused by uncontrollable heat diffusion enhances the immunosuppressive tumor microenvironment (ITM), consequently disabling the prevalent immune checkpoint blockade-combined immunotherapy against tumor recurrence. Herein, we successfully constructed an intratumorally synthesized Au bioreactor to disperse heat in thermally sensitive hydrogel-filled tumors and improve the energy utilization efficiency, which magnified the effective ablation zone (EAZ), counteracted iMWA, and simultaneously established and enhanced multiple biological process-regulated microwavegenetics. More significantly, we identified the extracellular matrix (ECM) viscosity as a general immune escape "target". After remodeling ECM, including ECM ingredients and cell adhesion molecules, this physical target was blocked by viscosity reprogramming, furnishing an effective tool to regulate the viscosity target. Thereby, such in situ Au bioreactor-enlarged EAZ and enhanced microwavegenetics reversed the immune-desert tumor microenvironment, mitigated ITM, secreted immune cell-attracting chemokines, recruited and polarized various immune cells, and activated or reactivated them like dendritic cells, natural killing cells, M1-type macrophages, and effector CD8+ or CAR-T cells. Contributed by these multiple actions, the in situ oncolytic Au bioreactors evoked CAR-T immunotherapy to acquire a considerably increased inhibition effect against tumor progression and recurrence after iMWA, thus providing a general method to enhance iMWA and CAR-T immunotherapy.

Facile synthesis of nitrogen-doped graphene quantum dots as nanocarbon emitters for sensitive detection of catechol.

Development of nanomaterial-based electrochemiluminescence (ECL) emitters is highly desirable for the fabrication and wide applications of ECL sensors. Herein, nitrogen-doped graphene quantum dots (NGQDs) were easily synthesized as nanocarbon emitters with anodic ECL for sensitive ECL determination of catechol (CC). Facile synthesis of NGQDs was easily achieved using molecular fusion of a carbon precursor in a one-step hydrothermal process. The synthesis has advantages of simple and convenient operation and high yield. The as-prepared NGQDs have uniform size, good crystallinity, single-layered graphene structure, and excitation-independent fluorescence. In the presence of hydrogen peroxide (H2O2), NGQDs exhibit high anodic ECL owing to the presence of functional hydrazide groups. As CC could significantly reduce the ECL intensity of NGQDs, sensitive determination of CC was realized with a linear range from 100 nM to 10 µM and 10 µM to 60 µM with a low limit of detection (LOD, 42 nM). The determination of CC in environmental water was also achieved with high reliability.

Intraparticle Double-Scattering-Decoded Sonogenetics for Augmenting Immune Checkpoint Blockade and CAR-T Therapy.

Genetically arming new chimeric antigen receptors (CARs) on T cells is a prevalent method to fulfill CAR-T immunotherapy. However, this approach fails to completely address the poor infiltration, complex immunosuppressive tumor microenvironment (ITM), and insufficient immune cells, which are recognized as the three dominant hurdles to discouraging the trafficking and persistence of CAR-T and immune checkpoint blockade (ICB) immunotherapies against solid tumors. To address the three hurdles, a sonoimmunity-engineered nanoplatform is designed in which a rattle-type-structured carrier enables intraparticle-double-scattering to generate massive reactive oxygen species (ROS) during the sonodynamic process. Abundant ROS accumulation can directly kill tumor cells, release antigens, and activate systematic immune responses for expanding effector T or CAR-T cells, while alleviating ITM via immunosuppressive macrophage polarization and reduction in pro-tumorigenic cytokine secretion. Furthermore, the co-loaded phosphodiesterase-5 inhibitors release nitric oxide (NO) to impel vascular normalization and open the infiltration barrier (IB) for allowing more T cells to enter into the tumor. Systematic experiments demonstrate the feasibility of such intraparticle-double-scattering-decoded sonogenetics in the sonoimmunity-engineered nanoplatforms for expanding effector T or CAR-T cells, thereby promoting their infiltration into tumors and alleviating ITM. These compelling actions lead to excellent CAR-T and ICB immunotherapies against solid tumors with repressed tumor metastasis.

Urine-Microenvironment-Initiated Composite Hydrogel Patch Reconfiguration Propels Scarless Memory Repair and Reinvigoration of the Urethra.

The harsh urine microenvironment (UME), as an inherent hurdle, endangers and renders urethral repair unreachable. Innovatively, the unfavorable UME is utilized as the design source to construct a UME-responsive 3D-printed hydrogel patch for realizing scarless memory repair, wherein laser-excited reactive oxygen species (ROS) production and mechanical strength elevation using chemically crosslinked silicon quantum dots are accessible. Intriguingly, the proposed composite scaffolds can respond to Ca2+ in urine, cause structure reconfiguration, and repress swelling to further enhance scaffold stiffness. Systematic experiments validate that ROS birth and unexpected stiffness elevation in such UME-responsive scaffolds can realize scarless memory repair of the urethra in vivo. Comprehensive mechanism explorations uncover that the activations of cell proliferation and collagen-related genes (e.g., MMP-1 and COL3A1) and the dampening of fibrosis-related (e.g., TGF-ß/Smad) and mechanosensitive genes (e.g., YAP/TAZ) are responsible for the scarless memory repair of such UME-responsive scaffolds via enhancing collagen deposition, recalling mechanical memory, decreasing fibrosis and inflammation, and accelerating angiogenesis. The design rationales (e.g., UME-initiated structure reconfiguration and antiswelling) can serve as an instructive and general approach for urethra repair.