Multicharged Foldable Plasma Membrane Probes for Precise Cancer Cell Discrimination and Fluorescence-Guided Surgery

This study addresses the critical clinical challenge of precise identification and treatment of cancer cells by proposing a novel targeting strategy based on differences in plasma membrane viscosity, and accordingly developing a multicharged foldable fluorescent probe, CSP-BP-CSP. Through rational structural design featuring a rigid bipyridine bridge and four cationic pyridinium units, the probe achieves high-affinity membrane anchoring with minimal cellular internalization, thereby significantly improving the signal-to-noise ratio and enabling long-term tracking. CSP-BP-CSP sensitively responds to viscosity variations between cancerous and normal cell membranes, allowing high-contrast specific cancer cell recognition and prolonged membrane labeling. Upon membrane damage, the probe translocates into the nucleus, enabling real-time monitoring of apoptosis. In animal models, CSP-BP-CSP exhibits sustained tumor-specific accumulation and has been successfully applied to fluorescence-guided precise tumor resection. Furthermore, the probe was employed to evaluate the antitumor efficacy of deuterium-enriched water, demonstrating its potential for theranostic integration. This work not only provides a new design strategy for membrane-anchored probes but also offers a versatile molecular platform for precise cancer diagnosis, intraoperative navigation, and treatment monitoring.