Magnetic nanobiopsy: A minimal technology for live cell biomolecular sampling

Abstract

Cellular heterogeneity is a fundamental determinant of precision medicine, governing transcriptional plasticity, lineage commitment, and adaptive programs that drive disease progression and therapeutic resistance. However, most molecular interrogation technologies remain inherently destructive, relying on bulk measurements that average cellular signals and systematically obscure rare but functionally decisive subpopulations. As a result, current approaches provide only static snapshots of complex cellular systems, preventing longitudinal analyses of dynamic molecular states and masking the contributions of relapse-initiating, phenotypically plastic, or therapy-resistant cells that ultimately dictate population fate. Here, we present magnetic nanobiopsy, a simple and scalable platform for minimally invasive, repeatable intracellular molecular sampling from living cells. Magnetically actuated nanocomposites (200 nm-1.4 {micro}m) enable efficient intracellular access and stable biomolecular capture while preserving cellular structural and functional integrity. High-resolution imaging and biochemical analyses confirm robust internalization and anchoring of intracellular biomolecules, while flow cytometry demonstrates that the retrieved cargo remains cell-specific and quantitatively representative of the parental heterogeneous population. By enabling longitudinal, single-cell-resolved molecular profiling within intact living populations, magnetic nanobiopsy bridges the gap between static bulk analyses and technically complex single-cell methods. This platform establishes a new framework for real-time investigation of cellular heterogeneity, adaptive responses, lineage diversification, and transient cell-state transitions, with broad applicability in cell biology, oncology, and biobanking. HighlightsO_LIMagnetic nanobiopsy enables non-destructive, longitudinal molecular sampling of living cell populations with high throughput and minimal operational complexity. C_LIO_LIThe nanoprobes bypass endo-lysosomal sequestration, directly interfacing with the cytosol to capture representative protein and RNA cargo via a membrane-preserving budding exit. C_LIO_LIQuantitative validation confirms that the retrieved molecular profiles faithfully mirror the heterogeneity and relative abundance of the parental cell population. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/705970v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1e0bee0org.highwire.dtl.DTLVardef@13a5b6org.highwire.dtl.DTLVardef@1e48f5dorg.highwire.dtl.DTLVardef@805b08_HPS_FORMAT_FIGEXP M_FIG C_FIG A magnetic nanobiopsy platform is presented for the longitudinal, non-destructive molecular sampling of living cell populations. Magnetically actuated nanocomposites directly access the cytosol--bypassing endo-lysosomal sequestration--to recruit a representative cargo of proteins and RNA through surface interactions and mechanical dragging. Guided by a changing external magnetic field, the molecularly loaded nanoparticles reversibly traverse the plasma membrane and exit via a controlled, budding-like mechanism that ensures cellular integrity. By preserving cell viability and population-level heterogeneity, this approach enables the retrieval of representative biomolecular cargo and the continuous monitoring of dynamic cellular states.