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We have synthesized lipidic prodrugs of celecoxib by grafting aliphatic chains to celecoxib through acyl sulfonamide (1), aryl sulfonyl carbamate (2) and aryl sulfonyl urea (3) chemical linkages. Their molecular formulas were confirmed through HR-MS and the formation of ester bond by FTIR and NMR spectroscopy. Nanoparticles of the different prodrugs were successfully formulated using emulsion evaporation method and DSPE-PEG2000as the only excipient. All nanoparticles were spherical and had a size between 130 and 160 nm, PdI ≤0.2 and negative Zeta potential values from −25 to −35 mV. In addition, they were stable upon storage at 4 °C and/or at room temperature for about a month (in shelf). Morphology of all nanoparticles were spherical-type as observed in transmission electron microscopy and scanning electron microscopy. The encapsulation efficiency of the prodrug was as high as 99% for all three corresponding prodrugs NPs. The nanoscale prodrugs 1–3,is reported for the first time. Moreover, all the characterization data (physicochemical and biological) regarding NPs is also unique. In addition, all prodrug nanoparticles have preserved in vitroanti-inflammatory activity when incubated with the THP-1 cell line activated with lipopolysaccharide (LPS). In vivostudies on a collagen induced arthritis murine model showed results: Prodrug 3NPs showed activity but were not as efficient as celecoxib in its free form, this might be due to no or very slow release of celecoxib form the prodrug 3NPs. To promote the reduction of inflammation using NPs would require to explore the possible administration of other prodrugs 1and 2in the future.