Author: Read, Clarissa ; Glocker, Bernhard ; Schütz, Desiree ; Rauch-Wirth, Lena ; Münch, Jan ; Walther, Paul ; Müller, Janis A ; Groß, Rüdiger ; Rode, Sascha

Retroviral gene transfer is the preferred method for stable, long-term integration of genetic material into cellular genomes, commonly used to generate chimeric antigen receptor (CAR)-T cells designed to target tumor antigens. However, the efficiency of retroviral gene transfer is often limited by low transduction rates due to low vector titers and electrostatic repulsion between viral particles and cellular membranes. To overcome these limitations, peptide nanofibrils (PNFs) can be applied as transduction enhancers. Among these, PNFs derived from the 12-mer peptide EF-C are well-investigated and commercially available. EF-C PNFs enhance transduction by forming EF-C PNFs/virus complexes that overcome electrostatic repulsion through their polycationic surface and interaction with cellular protrusions. However, the safe application of PNFs as transduction enhancers in gene therapeutic applications requires a fundamental understanding of their transduction-enhancing mechanisms, uptake, and degradation. In this study, we demonstrate that EF-C PNFs induce plasma membrane invaginations, increasing the membrane surface for viral attachment and reducing the distance to the nuclear membrane, thereby facilitating viral entry and transport to the nucleus. Furthermore, we identified macropinocytosis as the main entry pathway for EF-C PNFs and their subsequent degradation by lysosomal peptidases. The lysosomal degradation of EF-C PNFs prevents their accumulation as amyloid deposits, mitigating potential side effects and supporting their safe use in clinical applications.

01 Mar 2025·Advanced Materials

Self‐Sustained Biophotocatalytic Nano‐Organelle Reactors with Programmable DNA Switches for Combating Tumor Metastasis

Article

Author: Jiang, Shuai ; Sun, Hao ; Crespy, Daniel ; Han, Wenshuai ; Mao, Xiangzhao ; Landfester, Katharina ; Yu, Yingjie ; Ding, Jiayi ; Qiao, Bo

AbstractMetastasis, the leading cause of mortality in cancer patients, presents challenges for conventional photodynamic therapy (PDT) due to its reliance on localized light and oxygen application to tumors. To overcome these limitations, a self‐sustained organelle‐mimicking nanoreactor is developed here with programmable DNA switches that enables bio‐chem‐photocatalytic cascade‐driven starvation‐photodynamic synergistic therapy against tumor metastasis. Emulating the compartmentalization and positional assembly strategies found in living cells, this nano‐organelle reactor allows quantitative co‐compartmentalization of multiple functional modules for the designed self‐illuminating chemiexcited PDT system. Within the space‐confined nanoreactor, biofuel glucose is converted to hydrogen peroxide (H2O2) which enhances luminol‐based chemiluminescence (CL), consequently driving the generation of photochemical singlet oxygen (1O2) via chemiluminescence resonance energy transfer. Meanwhile, hemoglobin functions as a synchronized oxygen supplier for both glucose oxidation and PDT, while also exhibiting peroxidase‐like activity to produce hydroxyl radicals (·OH). Crucially, the nanoreactor keeps switching off in normal tissues, with on‐demand activation in tumors through toehold‐mediated strand displacement. These findings demonstrate that this nanoreactor, which is self‐sufficient in light and oxygen and precise in striking tumors, presents a promising paradigm for managing highly metastatic cancers.

01 Mar 2025·Advanced Materials

Machine Learning‐Assisted High‐Throughput Screening of Nanozymes for Ulcerative Colitis

Article

Author: Chen, Zhen ; Zhu, Zhiling ; Zhong, Liang ; Gao, Yubo ; Huang, Jiaxin ; Zhang, Qingyun ; Zhang, Ziqi ; Yang, Dongqin ; Qin, Jie ; Yu, Yixin ; Xu, Xudong ; Zhao, Xianguang ; Chen, Jiajie ; Tang, Xuemei

AbstractUlcerative colitis (UC) is a chronic gastrointestinal inflammatory disorder with rising prevalence. Due to the recurrent and difficult‐to‐treat nature of UC symptoms, current pharmacological treatments fail to meet patients' expectations. This study presents a machine learning‐assisted high‐throughput screening strategy to expedite the discovery of efficient nanozymes for UC treatment. Therapeutic requirements, including antioxidant property, acid stability, and zeta potential, are quantified and predicted by using a machine learning model. Non‐quantifiable attributes, including intestinal barrier repair efficacy and biosafety, are assessed via high‐throughput screening. Feature significance analysis, sure independence screening, and sparsifying operator symbolic regression reveal the high‐dimensional structure‐activity relationships between material features and therapeutic needs. SrDy2O4 with high stability, low toxicity, targeting ability, and reactive oxygen species (ROS) scavenging capability is identified, which reduces ROS production, lowers cytochrome C levels in cytoplasm, and inhibits apoptosis in intestinal epithelial cells by stabilizing the mitochondrial membrane potential. Mice treated with SrDy2O4 show improvements in colon length and body weight compared with dextran sodium sulfate salt‐treated model group. Transcriptomic and 16S rRNA sequencing analyses show that SrDy2O4 boosts beneficial gut bacteria, and decreases pathogenic bacteria, thereby effectively restoring gut microbiota balance. Moreover, SrDy2O4 offers the advantage of X‐ray imaging without side effects.

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