Exosomes, secreted by most cells, carry biological information and proteins that serve as noninvasive biomarkers for diagnosing and predicting disease progression and metastasis. However, the rapid isolation of high-purity exosomes from various biofluids, such as undiluted whole blood, plasma and serum, remains a challenge.

Acoustic methods, leveraging acoustic waves for gentle, contactless manipulation, offer a promising path. However, effectively isolating nanoscale particles such as exosomes directly from complex fluids like whole blood remains challenging. This difficulty is partly because of the acoustic diffraction limit, which restricts the tightness with which acoustic waves can be focused and controlled, thereby hindering the development of nano-separation techniques. 

In a study published in Science Advances, a research team led by Academician ZHENG Hairong and Prof. MENG Long from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences, collaborating with Prof. TIAN Zhenhua from Virginia Tech, USA, developed oscillating microbubble array–based metamaterials (OMAMs) for efficiently isolating exosomes from undiluted whole blood without labeling or pretreatment procedures.

OMAMs, multifunctional tunable ultradeep subwavelength metamaterials, enable the generation of multiple arbitrary acoustic fields with ultradeep subwavelength resolution, facilitate the switching between different acoustic energy fields, and allow for spatial tailoring of acoustic waves. Utilizing acoustic radiation forces and acoustic streaming, they capture larger particles like blood cells, effectively filtering the sample and allowing smaller exosomes to pass through.

To understand the particle trapping mechanisms, the researchers designed and developed the OMAMs platform as a highly efficient, reusable nanofilter with 46,750 microbubbles. This expanded the cross-scale capability of acoustic manipulation, in situ isolation of high-purity exosomes from whole blood samples.

It was found that OMAMs can isolate exosomes from undiluted whole blood in about three minutes with 93% purity, without requiring chemical reagents or pretreatments like centrifugation and filtration, and tuning microbubble oscillation amplitudes allows for further size-based isolation of exosome subpopulations within different mean diameters, demonstrating versatile acoustic tunability.

Compared to existing methods, the OMAMs platform offers a significantly faster, simpler, and potentially more cost-effective method to obtaining high-purity exosomes directly from clinical samples. This capability is crucial for advancing liquid biopsy diagnostics and developing exosome-based therapeutics.

“We anticipate that the OMAMs will benefit exosome-based biological research and clinical applications, as well as the development of tunable metamaterial-based acoustic lenses and transducers,” said Prof. MENG.