We develop membrane voltage nanosensors that are based on inorganic semiconductor nanoparticles. These voltage nanosensors are designed to self-insert into the cell membrane and optically record the membrane potential via the quantum confined Stark effect, with single-particle sensitivity. We present here the approach, design rules, and feasibility proves for this concept. With further improvements, semiconductor nanoparticles could potentially be used to study signals from many neurons in a large field-of-view over a long duration. Moreover, they could potentially report and resolve voltage signals on the nanoscale.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/044057 doi: bioRxiv preprint first posted online Mar. 16, 2016; 2 Recent advances in inorganic colloidal synthesis methods have afforded the construction of functional semiconductor (SC) nanoparticles (NPs) with ever-increasing control over size, shape, composition, and sophisticated heterostructures that exhibit unique photophysical, chemical and electronic properties 1,2,3,4 . This precise command of nanoscale materials synthesis has allowed for the exquisite engineering of excited state wavefunctions 5,6,7 , charge confinement, spatiotemporal control of charge-separated states 8 , and manipulation of Fermi levels and redox potentials. As a result, SC NPs have proved to be very useful in numerous applications in optoelectronics 9,10 , biological imaging 11 , sensing 12,13,14 , catalysis 15 , and energy harvesting 16 .Integrating inorganic nanomaterials with naturally evolved or synthetically evolved biological machineries could yield highly sophisticated hybrid nanobiomaterials that outperform biological-only or inorganic-only materials. Such materials could be self-assembled by biomolecular recognition while maintaining the superior properties of inorganic materials 17,18 . Selfassembly of inorganic components by biomolecular recognition could align components in defined geometries, spatial orientations, and structures. In addition, careful design and control of the organic-inorganic interface could afford hybridization of electronic states, enhancement of radiationless energy transfer or electron transfer, or matching of Fermi levels with redox potentials.Numerous functionalization and bioconjugation methods have been developed for the integration of inorganic-biological hybrid nanomaterials that are water soluble and biologically active 19,20 . Such hybrid nanomaterials have been used for in vitro biosensing, intra-cellular biological imaging 21 , single protein tracking in live cells 19 , and in vivo molecular imaging with favorable in vivo biodistribution and targeting properties (including renal clearance) 11,22,23 .Much fewer attempts have been made to functionalize nanomaterials in a way that will allow their integration into the membrane. The ability to impart membrane protein-like properties peer-reviewed...