Docetaxel (DTX) is an anticancer treatment widely used in the clinic for the treatment of various human malignancies, including Non-Small-Cell Lung Cancer (NSCLC). Its low water solubility and systemic toxicity, however, negatively impact the clinical application of such drug. In order to improve DTX solubility in biological fluids and decrease its adverse effects in patients, the scientific community is currently focusing on developing drug delivery systems where DTX is the payload. In this context, the present study aims at presenting a step forward in the development of platforms based on gold complexes for multifunctional approaches (theragnostic tools) and stimuli-responsive therapies. Tetrachloroauric acid (HAuCl) were complexed with the antitumor drug and dicarboxylic acid-terminated polyethylene-glycol (PEG) to form the nanometric complex named DTX-Au-PEG. Following reduction with sodium borohydride (NaBH), the DTX-Au-PEG complex formed hybrid-metal nanoparticles (DTX IN PEG-AuNPs), where DTX was protected in the gold core embedded within the polymer chains. To achieve therapeutic targeting, DTX-Au-PEG complex and DTX IN PEG-AuNPs were chemical combined with the human anti-EGFR polyclonal antibody, which recognizes the hERG1 channel aberrantly expressed on the membrane of human lung cancer cells. The active targeting was demonstrated by various analytical techniques (Raman and UV-vis spectroscopies); whereas, in vitro experiments on tissue-mimetic, three-dimensional (3D) tumoroids grown at the Air-Liquid Interface (ALI) demonstrated that DTX encapsulation within a gold core strongly influenced the drug efficacy, with a significant increase of the DTX therapeutic index when AuNPs were specifically targeted against EGFR. Collectively, our study demonstrated that a drug delivery system based on Au (III)-DTX complexes constitutes an encouraging chemical approach to build Au (III) complexes into real chemotherapeutic drugs for cancer treatment.Copyright © 2020 Elsevier B.V. All rights reserved.