We present a modular strategy to synthesize nanoparticle sensors equipped with dithiomaleimide-based, fluorescent molecular reporters capable of discerning minute changes in interparticle chemical environments based on fluorescence lifetime analysis. Three types of nanoparticles were synthesized with the aid of tailor-made molecular reporters, and it was found that protein nanoparticles exhibited greater sensitivity to changes in the core environment than polymer nanogels and block copolymer micelles. Encapsulation of the hydrophobic small-molecule drug paclitaxel (PTX) in self-reporting protein nanoparticles induced characteristic changes in fluorescence lifetime profiles, detected via time-resolved fluorescence spectroscopy. Depending on the mode of drug encapsulation, self-reporting protein nanoparticles revealed pronounced differences in their fluorescence lifetime signatures, which correlated with burst- vs diffusion-controlled release profiles observed in previous reports. Self-reporting nanoparticles, such as the ones developed here, will be critical for unraveling nanoparticle stability and nanoparticle-drug interactions, informing the future development of rationally engineered nanoparticle-based drug carriers.