Bioorthogonal Microbubbles with Antifouling Nanofilm for Instant and Suspended Enrichment of Circulating Tumor Cells

Integrating clinical rare cell enrichment, culture, and single-cell phenotypic profiling is currently hampered by the lack of competent technologies, which typically suffer from weak cell-interface collision affinity, strong nonspecific adsorption, and the potential uptake. Here, we report cells -on-a-bubble, a bioinspired, self-powered bioorthogonal micro -bubble (click bubble) that leverages a clickable antifouling nanointerface and a DNA-assembled sucker-like polyvalent cell surface, to enable instant and suspended isolation of circulating tumor cells (CTCs) within minutes. Using this biomimetic engineering strategy, click bubbles achieve a capture efficiency of up to 98%, improved by 20% at 15 times faster over their monovalent counterparts. Further, the buoyancy-activated bubble facilitates self-separation, 3D suspension culture, and in situ phenotyping of the captured single cancer cells. By using a multiantibody design, this fast, affordable micromotor-like click bubble enables suspended enrichment of CTCs in a cohort (n = 42) across three cancer types and treatment response evaluation, signifying its great potential to enable single-cell analysis and 3D organoid culture.

Automated summary

This study presents a biomimetic, self-powered bioorthogonal micro-bubble called cells-on-a-bubble (click bubble). It utilizes a clickable antifouling nanointerface and a DNA-assembled polyvalent cell surface to achieve rapid and suspended isolation of circulating tumor cells (CTCs) with a capture efficiency of up to 98%. The buoyancy-activated bubble also allows for self-separation, 3D suspension culture, and in situ phenotyping of captured single cancer cells, demonstrating its potential for single-cell analysis and 3D organoid culture.