A novel platform for the intracellular monitoring of key biological components has been developed, using three different nanoparticle fabrication technologies. These nano-optodes are termed PEBBLEs (Probes Encapsulated By Biologically Localized Embedding). The sensors, based on polyacrylamide, cross-linked decyl methacrylate, and silica-based sol-gel, have been characterized in aqueous solution and also tested in intracellular surroundings. Each matrix can be combined with specific "free dyes", ionophores, or enzymes to produce sensors selective for the biological component of interest. Spherical sensors less than 600 nm in diameter (and reducible to below 100 nm) have been made from all three matrices. Acrylamide-based sensors have been used to monitor intracellular pH and calcium (with proven selectivity over Mg2+). Decyl methacrylate has been successfully applied to intracellular potassium monitoring with probes 1,000 times more selective for potassium than sodium. Sol-gel has proven useful for monitoring intracellular oxygen at physiologically interesting concentrations. PEBBLEs, with a wide range of both simple and complex sensing schemes, provide a unique tool for minimally invasive intracellular monitoring, with many significant advantages over free dyes as well as over fiber-optic sensors.