<p>A fundamental goal in modern biology and precision medicine is to acquire rich, multi-omics-style information from cells, including transcriptomic, proteomic, metabolic and electrophysiological data, in real time and at single-cell resolution. However, current techniques often rely on destructive endpoint assays that require cell lysis, losing spatial, temporal and dynamic context. Nanoscale sensors offer a transformative solution by enabling minimally invasive, continuous monitoring of intracellular activities. Here we propose a spatial classification of intracellular sensing technologies—near cell, on cell and in cell—and use this framework to evaluate the sensing modalities on the basis of their invasiveness, signal fidelity and resolution. We highlight emerging sensor platforms that are capable of detecting ions, metabolites, electrical signals and mechanical changes, as well as artificial intelligence-driven strategies for decoding complex cellular data streams. We further consider the integration of these nanosensors into three-dimensional, physiologically relevant models such as organoids to create ‘smart organoids’ that report on their internal state autonomously and in real time. Finally, we discuss the major challenges in achieving intelligent intracellular sensing, including issues of sensor miniaturization, biocompatibility, multiplexing and three-dimensional integration. Together, these advances set the stage for a new era of dynamic, high-resolution cell profiling that can accelerate drug discovery, disease modelling and personalized medicine.</p>