Diamond quantum nanoprobes detect immune cell inflammation by sensing electric charge shifts, opening a new path for real-time single-cell monitoring in immunology and cancer research.
(Nanowerk Spotlight) A human macrophage detects a bacterial invader and mounts an inflammatory response in minutes. The chemical cascade that follows, from shifts in metabolism to bursts of reactive molecules and secretion of signaling proteins, reshapes the cell’s internal environment. Capturing that transformation as it unfolds, inside a single cell and without destroying it, has remained beyond the reach of existing tools.
Cytokine secretion assays average responses across thousands of cells, erasing individual behavior. Transcriptomic methods like RNA sequencing offer molecular detail but require destroying the cell, limiting measurements to a single endpoint. Flow cytometry demands extensive labeling and provides only coarse time resolution. Fluorescent reporters that tag specific molecules suffer from photobleaching, where repeated light exposure degrades the signal, and from drift that undermines long measurements.
Quantum sensors built from nitrogen-vacancy (NV) centers in diamond take a different tack. An NV center is an atomic-scale defect in a diamond crystal: a nitrogen atom sitting next to a vacant lattice site. This defect creates a quantum system whose electron spin states respond measurably to magnetic fields, temperature, and electric fields, and whose state can be read out using laser light.
Research groups have used NV centers to detect magnetic signatures from bacteria, record action potentials in neurons, and measure nanoscale temperature gradients in developing embryos.
A persistent obstacle has limited the technology’s usefulness in living systems. Each diamond nanoparticle contains roughly 100 NV centers oriented in random directions. When an external electric field acts on these randomly pointing spins, individual responses cancel out, producing spectral broadening rather than a clean, trackable signal. This averaging effect has blocked practical use of NV ensembles for electric-field sensing inside cells.
Separately, multiple groups have reported shifts in a key NV spectral parameter during cellular measurements and interpreted them as evidence of intracellular temperature changes, sometimes implying heating of several degrees Celsius within a single cell. Such values are difficult to reconcile with basic thermodynamics, and researchers have not agreed on their origin.
A study now published in Advanced Materials (“Probing Cellular Activity Via Charge‐Sensitive Quantum Nanoprobes”) by a team based primarily at the University of Chicago and the University of Iowa addresses both challenges. The researchers present a quantum sensing approach that converts what was previously treated as noise, the interaction between a diamond nanoparticle’s surface and its chemical surroundings, into a quantifiable signal of cellular activity.
Their method detects inflammatory activation in individual macrophages, the immune cells responsible for recognizing and responding to bacterial threats, by tracking shifts in a quantum property called the zero-field splitting (ZFS). This parameter represents the energy gap between spin states in the NV center’s ground state and responds to both temperature and electric fields, which is why its interpretation has been so debated.
Probing macrophage inflammation with charge sensitive quantum nanoprobes. Cells were imaged following incubation with bare (a) and core-shell (b) particles. (Image: Adapted from DOI:10.1002/adma.202505107, CC BY)
The theoretical advance at the core of this work involves a term in the equations governing NV energy levels that earlier biological sensing studies neglected. Standard models describe how electric field components along and perpendicular to the NV axis couple to the spin. These couplings depend on orientation, and across a randomly oriented ensemble they average to zero, producing broadening but no net frequency shift.
The new model incorporates a secondary transverse dipole term, labeled d′, estimated to be comparable in magnitude to the primary transverse term. This d′ term contributes a second-order energy correction that does not cancel across random orientations. In practical terms, the sensor now produces a measurable frequency shift regardless of how the nanoparticle happens to be oriented, and that shift grows quadratically with local electric field strength.
The electric field driving this shift originates inside the diamond particle itself. Surface interactions with the surrounding chemical environment alter the charge states of nitrogen defects embedded near the particle’s surface. When electrons transfer from the diamond lattice to the environment, the internal charge distribution rearranges, modifying the electric field that the NV centers experience.
Experimental validation began with 70 nm bare diamond nanocrystals in phosphate-buffered saline (PBS), a solution that mimics the ionic conditions of biological fluids. After approximately one hour of laser illumination at roughly 0.1 mW/μm², the ZFS shifted systematically to lower frequencies by an average of −0.45 MHz, accompanied by asymmetric spectral broadening. Both observations matched the model’s predictions for charge depletion. No such shifts appeared in air or pure water, confirming that the chemical environment drives the effect.
A critical control used diamond nanocrystals coated with a 15 nm silica shell. These core-shell particles showed essentially no ZFS drift under identical PBS conditions. Stability analysis confirmed that core-shell particles reached a noise floor of 0.847 kHz, while bare particles displayed a clear drift at longer timescales.
The silica coating also reduced biological side effects. When the team incubated both particle types with RAW macrophages, a standard murine immune cell line, core-shell particles caused significantly less membrane damage, lower inflammatory signaling, and reduced secretion of the inflammatory cytokine TNF-α across concentrations from 10 to 200 μg mL⁻¹.
The central biological demonstration involved stimulating macrophages with lipopolysaccharide (LPS), a bacterial surface molecule that triggers a strong inflammatory response. All five bare nanocrystals measured inside LPS-stimulated cells, spread across four separate cells, exhibited negative ZFS drifts over 200 seconds, averaging −0.27 ± 0.03 MHz. If this shift reflected temperature alone, it would imply cell heating of 3.62 °C, a result that is thermodynamically implausible for a single cell. Under the charge-transfer framework, it instead reflects an effective surface potential decrease of approximately 450 mV.
Core-shell particles inside identically treated cells showed no comparable drift, providing strong evidence that the measured signal reflects surface charge interactions rather than temperature. Additional controls ruled out pH variations and protein adsorption as primary causes. Bare particles incubated with lysate from LPS-stimulated cells reproduced shifts closely matching those in live cells, with a mean of −296 ± 51 kHz, while core-shell particles in the same lysate showed no significant change. Exposure to hydrogen peroxide at concentrations of 1–500 μM produced moderate ZFS shifts, implicating oxidative stress as a contributing factor, though the smaller magnitude suggests other cellular components also play a role.
The study represents the first demonstration that charge-transfer sensing through diamond nanoparticles can detect an immune cell’s inflammatory state. The charge-sensing framework also provides a physically consistent alternative to the contested interpretation that large ZFS shifts in cellular measurements reflect intracellular temperature swings. The core-shell architecture serves a dual purpose: it suppresses charge-transfer artifacts, improving NV-based thermometry, while simultaneously reducing inflammation and toxicity caused by the sensor itself.
The team reports that it is now applying this approach to distinguish between different macrophage polarization states and to monitor T-cell-induced killing of tumor cells, work that could extend quantum sensing from single-cell physics experiments into immunology and oncology.
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