Fluidic Multivalent Membrane Nanointerface Enables Synergetic Enrichment of Circulating Tumor Cells with High Efficiency and Viability

Abstract

The ubiquitous biomembrane interface, with its dynamic lateral fluidity, allows membrane-bound components to rearrange and localize for high-affinity multivalent ligand–receptor interactions in diverse life activities. Inspired by this, we herein engineered a fluidic multivalent nanointerface by decorating a microfluidic chip with aptamer-functionalized leukocyte membrane nanovesicles for high-performance isolation of circulating tumor cells (CTCs). This fluidic biomimetic nanointerface with active recruitment-binding afforded significant affinity enhancement by 4 orders of magnitude, exhibiting 7-fold higher capture efficiency compared to a monovalent aptamer functionalized-chip in blood. Meanwhile, this soft nanointerface inherited the biological benefits of a natural biomembrane, minimizing background blood cell adsorption and maintaining excellent CTC viability (97.6%). Using the chip, CTCs were successfully detected in all cancer patient samples tested (17/17), suggesting the high potential of this fluidity-enhanced multivalent binding strategy in clinical applications. We expect this bioengineered interface strategy will lead to the design of innovative biomimetic platforms in the biomedical field by leveraging natural cell–cell interaction with a natural biomaterial.

Bioinspired DNA Nanointerface with Anisotropic Aptamers for Accurate Capture of Circulating Tumor Cells

“…[13][14][15] Several groups have demonstrated the engineering of multivalent aptamer for a lower dissociation constant, giving rise to highly efficient CTCs capture. [16][17][18][19][20][21] As a recent example, one study has taken advantage of DNA framework to control the spatial organization of trivalent aptamers against EpCAM (epithelial cell adhesion molecule). Such topological engineering not only merely increases the ligand binding affinity with the membrane receptors, but also prevents the aptamer from endocytosis by cells, which has been evaluated by improved CTCs capture.…”

Nanoparticle‐Enabled Dual Modulation of Phagocytic Signals to Improve Macrophage‐Mediated Cancer Immunotherapy

“…This phenomenon strongly suggested that the targeting effect of the nanoparticle was mediated by aCD47. Additionally, aCD47‐conjugated NPs showed significantly higher binding affinity to 4T1 cells in comparison with free aCD47 due to the multivalent effect of NP‐based systems, [ 27–28,34 ] which was demonstrated by the values of the dissociation constant ( K D ) (Figure S3, Supporting Information).…”

“…[ 25 ] Through interaction with the low‐density lipoprotein receptor‐related protein 1 (LRP1) on macrophages, CALR acts as an “eat me” signal to promote macrophage engulfment of tumor cells. [ 26–28 ] The expression level of CALR is a key determinant of the effectiveness of CD47‐SIRPα axis blockade. [ 29–30 ] When the surface exposure of CALR is low, blockade of CD47‐SIRPα may not elicit sufficient phagocytosis.…”

Detection of circulating tumor cells: Advances and critical concerns (Review)

“…A recent emerging novel engineering strategy is the fabrication of biomimetic nanoparticles that combine synthetic nanomaterials with natural biomaterials, such as the membranes of leukocytes (43), RBCs (44) and platelets (45). A fluidic and multivalent engineered nanointerface decorating a microfluidic chip with aptamer-functionalized leukocyte membrane nanovesicles has been described (46). Platelet-leukocyte hybrid membrane-coated magnetic nanoparticles were designed with cell membranes modified with anti-EpCAM for the high-performance isolation of CTCs (45).…”

“…The combination of nanoparticles and cell membranes significantly decreases the nonspecific adsorption and scavenging probability of nanoparticles (45). In addition, placing a layer of soft yet flexible nanovesicles between the cell and capture substrate, which serves as a cushion, can minimize cell damage resulting from interfacial collision (46). Application of microfluidics technology for isolation and detection of CTCs.…”