Luca Salvigni

Misfolded alpha-Synuclein (α-Syn) accumulation is the defining molecular pathology of Parkinson’s disease (PD), yet blood-based assays remain challenged by the high background of peripheral α-Syn originating mainly from red blood cells. Neuronal extracellular vesicles (EVs) circulating in blood offer a biologically enriched source of brain-derived α-Syn proteoforms, but their ultralow abundance has hindered reliable detection. Here, we introduce an organic electrochemical transistor–based multiparametric diagnostic assay that simultaneously detects total, aggregated, and serine-129–phosphorylated α-Syn proteoforms in serum L1CAM ⁺ EVs. The platform achieves low femtomolar sensitivity in buffer and robust analytical performance in clinical specimens. In a cohort of 66 individuals, including prodromal and clinically diagnosed patients with PD, combining the three proteoform readouts distinguished PD from controls with 90.9% accuracy (88.6% sensitivity and 90.9% specificity). By electronically amplifying and resolving multiple neuronal α-Syn signatures in blood, this assay enables a minimally invasive diagnostic tool for early-stage PD and provides a path toward therapeutic intervention during the window when disease-modifying treatments are likely to be most effective.

Organic electrochemical transistors (OECTs) combine amplification and transduction, making them attractive for biochemical sensing. Yet, the fundamental mechanisms by which OECTs convert biochemical binding events into electrical signals remain poorly understood, limiting their optimization and broader use in biomarker detection. Here, we demonstrate how binding-induced changes in surface potential and capacitance at OECT interfaces can either translate into amplified output signals or result in destructive interaction and signal cancellation. By integrating electrochemical principles with solid-sate device physics, we establish a rational sensing model and provide design and operation rules to maximize biosensor performance. These include guidelines for operating voltage selection, optimal output signal choice, gate electrode geometry, and channel material properties (n-type versus p-type, doped versus undoped). This framework can enable the rational design of OECT-based sensors with enhanced response, lower detection limits, and improved resistance to interference, paving the way for reliable and versatile use of these devices as the enabler of next generation, high-performance biosensors.

Timely and accurate diagnosis of respiratory infections is complicated by the symptomatic overlap between highly transmissible pathogens such as respiratory syncytial virus (RSV), influenza A (IAV), and influenza B (IBV), highlighting the need for rapid and reliable diagnostics. Here, we report a time‐multiplexed nanobody‐functionalized organic electrochemical transistor (OECT) biosensor for the sensitive detection of RSV, IAV, and IBV directly from unprocessed saliva samples. The platform integrates arrays of nanobody‐functionalized gate electrodes that are exposed in parallel to a single sample and sequentially addressed through a shared transistor channel. We characterize nine previously reported nanobodies and immobilize the best‐performing ones using an oriented SpyDirect self‐assembly strategy. The nanobody‐functionalized gate electrodes are paired with a high‐performance p‐type organic mixed ionic‐electronic conductor channel, enabling efficient signal transduction. The sensor achieves a limit of detection of ca. 1 f m and identifies viral targets within 15 min, without sample preprocessing. In a clinical validation using 17 samples, the platform demonstrated 100% specificity, 86.7% sensitivity, and 88.2% overall accuracy. By combining highly specific nanobodies, a high‐gain transducer, customized surface pre‐treatment, and a time‐multiplexed multi‐gate architecture, this approach provides a scalable and user‐friendly platform for point‐of‐care virus detection.

Organic electrochemical transistors have emerged as a promising alternative to traditional 2/3 electrode setups for sensing applications, offering in-situ transduction, electrochemical amplification, and noise reduction. Several of these devices are designed to detect potentiometric-derived signals. However, potentiometric sensing should be performed under open circuit potential conditions, allowing the system to reach thermodynamic equilibrium. This criterion is not met by conventional organic electrochemical transistors, where voltages or currents are directly applied to the sensing interface, that is, the gate electrode. In this work, we introduce an organic electrochemical transistor sensing configuration called the potentiometric‑OECT (pOECT), which maintains the sensing electrode under open circuit potential conditions. The pOECT exhibits a higher response than the 2-electrode setup and offers greater accuracy, response, and stability compared to conventional organic electrochemical transistors. Additionally, it allows for the implementation of high-impedance electrodes as gate/sensing surfaces, all without compromising the overall device size.