LAUSR

&NA; The overexpression of CD44 in cancer cells reroutes number of oncogenic pathways including the central Pi3K/Akt/NF‐kB pathway leading to cancer progression and malignancy. Herein, we developed hyaluronic acid‐modified poly(DL‐lactic‐co‐glycolic acid)‐poly (ethylene glycol) nanoparticles (PLGA‐PEG‐HA NPs) for targeted delivery of TTQ (thio‐tetrazolyl analog of a clinical candidate, IC87114) to CD44 overexpressing cancer cells. The PLGA‐PEG co‐polymer was synthesized and characterized by NMR and FTIR. The co‐polymer based nanoparticles were prepared by solvent evaporation method and hyaluronic acid (HA) was conjugated on to the nanoparticle surface via EDC/NHS chemistry. The PLGA‐PEG–HA NPs had a desirable particle size (< 200 nm) with reduced polydispersibility and exhibited spherical shape under atomic force microscope (AFM). In vitro cytotoxicity and cellular uptake studies demonstrated higher cytotoxicity and enhanced intracellular accumulation of PLGA‐PEG‐HA NPs compared to PLGA‐PEG NPs in high CD44 expressing MiaPaca‐2 cells compared to MDA‐MB‐231 and MCF7 cells. At the molecular level, the PLGA‐PEG‐HA NPs were found to be inducing premature senescence with increase in senescence associated &bgr;‐galactosidase activity and senescence specific marker p21 expression through modulation of Pi3K/Akt/NF‐kB signaling pathway in MiaPaca‐2 cells. These findings collectively indicated that HA‐modified nanoparticles might serve as a promising nanocarrier for site‐specific drug delivery, and can be explored further to increase the therapeutic efficacy of anticancer drugs via targeting to CD44 over‐expressing cancer cells. Graphical abstract Figure. No caption available.