Real-time SERS analysis of programmed cell death patterns based on black Phosphorus–gold nanoparticles

Programmed cell death (PCD) plays a crucial role in the biological processes of living organisms and occurs in various forms, such as apoptosis, necroptosis and ferroptosis. However, traditional methods for PCD analysis are time-consuming and complex. In this paper, we propose a facile surface-enhanced Raman spectroscopy (SERS)-based strategy for the real-time analysis of three PCD patterns utilizing black phosphorus–gold nanoparticles (BP–Au NPs) as the ultrasensitive unlabeled Raman probe. BP–Au NPs, which possess excellent biocompatibility, are capable of detecting dye molecules at concentrations as low as [Formula: see text][Formula: see text]M and remain stable for at least one week in different physiological environments. In view of this, BP–Au NPs-based SERS technique can distinguish the tiny differences in the molecular fingerprints of cancer cells undergoing three PCD patterns (apoptosis, necroptosis and ferroptosis) triggered by doxorubicin, shikonin and erastin, respectively. We also have real-time monitoring of the intracellular molecular events during PCD, which spy the fluctuations of some typical SERS bands assigned to protein, DNA and lipid, revealing the unique phenotypic characteristics of each PCD pattern. This strategy provides a detailed and comprehensive analysis of the mechanisms of drug-induced PCD at the Raman level.