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Cancer remains one of the leading causes of morbidity and mortality worldwide, with conventional therapies often associated with significant side effects and the development of tumour resistance. In this context, the repositioning of drugs such as metformin, a hypoglycaemic agent with antineoplastic properties has emerged as a promising strategy to reduce costs and development time for new treatments. The aim of this study was to develop gliadin and hyaluronic acid (HA) nanoparticles (NPs) loaded with metformin (Gliadin_Metf_HA), with the aim of actively targeting the tumour microenvironment through HA-CD44 interaction, a receptor overexpressed in cancer cells. The specific objectives included: (i) evaluating in silico the molecular interaction between metformin and the HA-binding domain of the CD44 receptor (PDB ID: 1UUH) by molecular docking; (ii) synthesising and characterising Gliadin_Metf_HA NPs by flash nanoprecipitation (FNP); and (iii) evaluating their stability, encapsulation efficiency (E.E), controlled drug release, in vitro biocompatibility and qualitative internalisation of NPs. Computer simulations carried out with AutoDock Vina and analysed in PyMOL showed that metformin has a moderate affinity (-4.4 kcal/mol) for CD44, forming hydrogen bonds with key residues (PHE30, GLU75, THR27, THR76), which simulate a potential as a ligand for this receptor. The NPs were synthesised by FNP, using Gliadin (2.5 mg/mL in 80% ethanol) and HA (0.5 mg/mL in water), and characterised in terms of hydrodynamic size (~200 nm), polydispersity index (PDI < 0.4), zeta potential (~ -25 mV) and stability under different conditions (4°C for 30 days and after freeze-drying with 10% mannitol). The E.E of metformin was 96 ± 0.15%, with a drug load (DL) of 2.34 ± 0.27%. In vitro release tests in simulated lung fluid (SLF) showed a pH-dependent profile, with sustained release at pH 6.8 (tumour condition) and faster release at pH 7.4 (physiological condition). Cytotoxicity tests (MTT) on human fibroblasts (NHDF) and lung cancer cells (A549) revealed high biocompatibility (viability >70% in NHDF) and selective antitumoral effect in A549 viability for 120h. CD44-mediated cell internalisation was confirmed by fluorescence microscopy. It is concluded that Gliadin_Metf_HA NPs represent a promising delivery system for targeted antitumour therapy, combining high stability, controlled release and selective cytotoxicity.