分子探针 z-bio 2025-03-10 398

　　Figure (a-c) Schematic diagram of molecular assembly probes that can cascade in response to the tumor microenvironment and their research; Fluorescence imaging and signal intensity changes of in situ pancreatic cancer in (d, e) mouse model

　　With the support of National Natural Science Foundation of China projects (approval numbers: 22274074, 2137003) and other grants, the team led by Ye Deju from Nanjing University has made new progress in the study of molecular probes in vivo. The related research results, titled "Tandem controlled lysosomal assembly of nanofibers induces pyroptosis for cancer immunotherapy", were published on February 18, 2025 in the journal Nature Nanotechnology. Paper link: https://doi.org/10.1038/s41565-025-01857-9 .

　　Molecular probes are key tools for precise detection and regulation of biomolecules, widely used in fields such as disease diagnosis, target validation, drug development, and molecular mechanism research. However, the complex biological tissue barriers, highly dynamic environment, and the presence of a large number of interfering substances in vivo limit the specificity of probes and the efficiency of target tissue delivery, which poses great difficulties for precise detection and regulation of biomolecules in the current complex living environment.

　　In response to the above challenges, the team has developed a molecular assembly probe (NP-NH-D5) that can cascade in response to the tumor microenvironment through modular design of molecules and precise regulation of intermolecular assembly, combined with surface charge flipping and structural morphology transformation strategies. This probe can sequentially recognize extracellular MMP-2 enzyme and intracellular reducing biomolecules (GILT enzyme and glutathione) in the tumor microenvironment, and activate them step by step to regulate the surface charge, size, and structure of the probe, thereby achieving efficient targeted delivery to tumor cells. This process effectively enhances the uptake efficiency of the probe in the tumor and significantly prolongs the retention time within the tumor, thereby enhancing the tumor imaging signal and achieving precise localization of in situ and distal metastatic tumor foci in the mouse model.

　　On this basis, the above team further explored the cascade process of "targeting assembly destruction activation" of probes in tumor cells, elucidating the mechanism by which in situ assembled nanofiber structures rapidly destroy tumor cell lysosomes and activate GSDMD dependent cell pyroptosis molecules. This provides an innovative chemical strategy for precise localization and targeted immunotherapy of tumor lesions in complex living environments.