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[Display omitted] • Nanocarrier composing Ag core and HA shell was prepared for targeting DOX delivery. • Synergistic effect of Ag, DOX and HA significantly improved the anticancer activity. • The nanocarrier exhibited the pH-responsive and tumor-targetable properties. • The nanocarrier enhanced antitumor efficacy and reduced the toxicity of free DOX. • The Ag NPs@HA is potential carrier for targeting delivery of anticancer drugs. Although various nanocarriers have been developed to deliver anticancer drugs to the target tumors, it is still remaining great challenges, including burst release, non-specific targetability and insufficient therapeutic efficacy. Herein, we prepared a multifunctional nanoparticle composed of Ag core and hyaluronic acid shell (Ag NPs@HA) for stimultaneously intracellular delivery of Doxorubicin (DOX) and Ag NPs to improve the anticancer therapeutic efficacy. For our approach, Ag NPs was simply synthesized via the redox reaction between Ag+ ions and catechol group of functional HA, and DOX was subsequently loaded into the HA-coated Ag NPs through the interaction between the remaining catechol groups and DOX (Ag NPs@HA/DOX). The particles exhibited uniform morphology, good biocompatibility to normal cells, and pH-sensitive drug release. Notably, thanks to the specific interaction of HA and CD44 receptor-overexpressing cancer cells, Ag NPs@HA/DOX could dramatically improve the anti-tumor efficacy in vitro as well as in vivo mimicking 3D spheroid model, compared to the free DOX. Moreover, Ag NPs@HA/DOX exhibited superior tumor supression in vivo on a HELA-xenografted mouse model, while minimizing the systemic toxicity of free DOX. From the obtained results, we suggest Ag NPs@HA as potential nanocarrier for targeting delivery of various therapeutic drugs in anticancer therapy. [ABSTRACT FROM AUTHOR]