Osimertinib (OMB) is an irreversible TK inhibitor approved to treat cancers with epidermal growth factor receptor (EGFR) mutations. Despite its high solubility and absorption, its poor tumor selectivity and off-target systemic toxicity pose problems to its effectiveness and safety. This study aimed to enhance tumor-targeted delivery of OMB via CD44 targeting by developing an effective OMB-nanoliposomal formulation for overcoming challenges associated with conventional OMB delivery. OMB-loaded

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... posomal formulations were developed using a freeze-drying method, and all were successfully characterized, including in-vitro OMB release. non-small cell lung cancer models H1975 and PC-9 cells were used to study hyaluronan-CD44 receptor targeting, cellular uptake, and cytotoxicity. All formulations exhibited superior characteristics of size, zeta potential, and PDI with high encapsulation efficiency. Among all formulations, mPEG-hyaluronic acid (HA) (mds)-OMB-LPs demonstrated long-term in-vitro drug release, with a cumulative % drug release of 99.99% ± 2.58% up to 72 hours stating the sustained release of OMB at pH 7.4. The cellular uptake and cytotoxicity of mPEG-HA coated LPs at a 1:1 was greater than those of OMB-LPs, as well as Tagrisso in both the cells overexpressing CD44, whereas the effect was lower in PC-9 cells having low CD44 expression. It is evident from these findings that successful liposomal formulations are taken up by cells via CD44mediated processes. As compared with plain OMB solution, mPEG-HA-OMB-LPs increased in-vitro accumulation and cytotoxicity in both H1975 and PC-9 cells with activating EGFR mutations.