A class of core-shell nanoparticles possessing a layer of biocompatible shell and hydrophobic core with embedded oxygen-sensitive platinum-porphyrin (PtTFPP) dyes is developed via a radical-initiated microemulsion co-polymerization strategy. The influences of host matrices and the PtTFPP incorporation manner on the photophysical properties and the oxygen-sensing performance of the nanoparticles are investigated. Self-loading capability with cells and intracellular-oxygen-sensing ability of the as-prepared nanoparticle probes in the range 0%–20% oxygen concentration are confirmed. Polymeric nanoparticles with optimized formats are characterized by their relatively small diameter (<50 nm), core-shell structures with biocompatible shells, covalent-attachment-imparted leak-free construction, improved lifetime dynamic range (up to 44 μs), excellent storage stability and photostability, and facile cell uptake. The nanoparticles’ small sensor diameter and core-shell structure with biocompatible shell make them suitable for intracellular detection applications. For intracellular detection applications, the leak-free feature of the as-prepared nanoparticle sensor effectively minimizes potential chemical interferences and cytotoxicity. As a salient feature, improved lifetime dynamic range of the sensor is expected to enable precise oxygen detection and control in specific practical applications in stem-cell biology and medical research. Such a feature-packed nanoparticle oxygen sensor may find applications in precise oxygen-level mapping of living cells and tissue.