Circulating tumor cells (CTCs) are detected in approximately 30% of metastatic non-small-cell lung cancer (NSCLC) cases using the CellSearch system, which relies on EpCAM immunomagnetic enrichment and Cytokeratin detection. This study evaluated the effectiveness of immunomagnetic enrichment targeting oncofetal chondroitin sulfate (ofCS) using recombinant VAR2CSA proteins (rVAR2) to improve the recovery of different NSCLC cell lines spiked into lysed blood samples. Four NSCLC cell lines—NCI-H1563, A549, NCI-H1792, and NCI-H661—were used to assess capture efficiency. The results demonstrated that the combined use of anti-EpCAM antibody and rVAR2 significantly enhanced the capture efficiency to an average of 88.2% compared with 40.6% when using only anti-EpCAM and 56.6% when using only rVAR2. These findings suggest that a dual-marker approach using anti-EpCAM and rVAR2 can provide a more robust and sensitive method for CTC enrichment in NSCLC, potentially leading to better diagnostic and prognostic outcomes.

Biomimetic membrane interface engineering constructs functionalized detection platforms by incorporating natural cell membranes, synthetic lipids, or hybrid membranes. The primary purpose of this strategy is to minimize background interference while leveraging intrinsic membrane properties for effective target interaction. Applications are diverse, ranging from the high‐purity separation of circulating tumor cells (CTCs) to the efficient isolation of extracellular vesicles (EVs), as well as the subsequent detection of EV‐derived contents (e.g., miRNA, protein, and mRNA) via membrane fusion mechanisms. Conceptually, this approach serves as a robust bridge between synthetic materials and biological systems. Its major advantages lie in the significant reduction of non‐specific binding and the unique capability to facilitate both target capture and internal cargo analysis. However, challenges such as complex preparation processes, stability issues, and the dependence on functional modifications to address significant tumor heterogeneity remain to be resolved. This review summarizes recent progress, analyzes these critical issues, and outlines future directions.